Ocular delivery systems and methods

ABSTRACT

Described here are systems and methods for accessing Schlemm&#39;s canal and for delivering an ocular device, tool, or fluid composition therein. The ocular devices may maintain the patency of Schlemm&#39;s canal without substantially interfering with transmural fluid flow across the canal. The fluid composition may be a viscoelastic fluid that is delivered into the canal to facilitate drainage of aqueous humor by disrupting the canal and surrounding trabeculocanalicular tissues. Some systems described here may be configured to cut or tear the trabecular meshwork with the body of an elongate member located within Schlemm&#39;s canal. Other tools for disrupting these tissues and minimally invasive methods for treating medical conditions associated with elevated intraocular pressure, including glaucoma, are also described.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/675,580, filed Mar. 31, 2015, which issued as U.S. Pat. No.10,299,958, the disclosure of which is hereby incorporated by referencein its entirety.

FIELD

Described here are systems and methods for accessing Schlemm's canal inan eye and for delivering an ocular device, tool, or fluid compositiontherein. The ocular devices may maintain the patency of Schlemm's canalwithout substantially interfering with transmural, transluminal,circumferential, or longitudinal aqueous humor fluid flow across thecanal. The tools delivered may be used to disrupt the trabecularmeshwork. The fluid composition may be a viscoelastic fluid that isdelivered into the canal or aqueous collector channels to facilitatedrainage of aqueous humor by dilating the canal, disruptingjuxtacanalicular meshwork and the adjacent wall of Schlemm's canal,and/or increasing aqueous permeability through the trabeculocanalicular,or transmural, outflow pathway. Minimally invasive methods for treatingmedical conditions associated with elevated intraocular pressure,including glaucoma, are also described.

BACKGROUND

Glaucoma is a potentially blinding disease that affects over 60 millionpeople worldwide, or about 1-2% of the population. Typically, glaucomais characterized by elevated intraocular pressure. Increased pressure inthe eye can cause irreversible damage to the optic nerve which can leadto loss of vision and even progress to blindness if left untreated.Consistent reduction of intraocular pressure can slow down or stopprogressive loss of vision associated with glaucoma.

Increased intraocular pressure is generally caused by sub-optimal effluxor drainage of fluid (aqueous humor) from the eye. Aqueous humor orfluid is a clear, colorless fluid that is continuously replenished inthe eye. Aqueous humor is produced by the ciliary body, and thenultimately exits the eye primarily through the trabecular meshwork. Thetrabecular meshwork extends circumferentially around the eye at theanterior chamber angle, or drainage angle, which is formed at theintersection between the peripheral iris or iris root, the anteriorsclera or scleral spur and the peripheral cornea. The trabecularmeshwork feeds outwardly into Schlemm's canal, a narrow circumferentialpassageway generally surrounding the exterior border of the trabecularmeshwork. Positioned around and radially extending from Schlemm's canalare aqueous veins or collector channels that receive drained fluid. Thenet drainage or efflux of aqueous humor can be reduced as a result ofdecreased facility of outflow, decreased outflow through the trabecularmeshwork and canal of Schlemm drainage apparatus, increased episcleralvenous pressure, or possibly, increased production of aqueous humor.Flow out of the eye can also be restricted by blockages or constrictionin the trabecular meshwork and/or Schlemm's canal and its collectorchannels.

Glaucoma, pre-glaucoma, and ocular hypertension currently can be treatedby reducing intraocular pressure using one or more modalities, includingmedication, incisional surgery, laser surgery, cryosurgery, and otherforms of surgery. In general, medications or medical therapy are thefirst lines of therapy. If medical therapy is not sufficientlyeffective, more invasive surgical treatments may be used. For example, astandard incisional surgical procedure to reduce intraocular pressure istrabeculectomy, or filtration surgery. This procedure involves creatinga new drainage site for aqueous humor. Instead of naturally drainingthrough the trabecular meshwork, a new drainage pathway is created byremoving a portion of sclera and trabecular meshwork at the drainageangle. This creates an opening or passage between the anterior chamberand the subconjunctival space that is drained by conjunctival bloodvessels and lymphatics. The new opening may be covered with scleraand/or conjunctiva to create a new reservoir called a bleb into whichaqueous humor can drain. However, traditional trabeculectomy procedurescarry both short and long term risks. These risks include blockage ofthe surgically-created opening through scarring or other mechanisms,hypotony or abnormally low intraocular pressure, expulsive hemorrhage,hyphema, intraocular infection or endophthalmitis, shallow anteriorchamber angle, macular hypotony, choroidal exudation, suprachoroidalhemorrhage, and others.

One alternative is to implant a device in Schlemm's canal that maintainsthe patency of the canal or aids flow of aqueous humor from the anteriorchamber into the canal. Various stents, shunts, catheters, andprocedures have been devised for this purpose and employ an ab-externo(from the outside of the eye) approach to deliver the implant orcatheter into Schlemm's canal. This method of placement is invasive andtypically prolonged, requiring the creation of tissue flaps and deepdissections to access the canal. Additionally, it is very difficult formany surgeons to find and access Schlemm's canal from this externalincisional approach because Schlemm's canal has a small diameter, e.g.,approximately 50 to 250 microns in cross-sectional diameter, and it maybe even smaller when collapsed. One such procedure, ab-externocanaloplasty, involves making a deep scleral incision and flap, findingand unroofing Schlemm's canal, circumnavigating all 360 degrees of thecanal with a catheter from the outside of the eye, and either employingviscoelastic, a circumferential tensioning suture, or both to helpmaintain patency of the canal. The procedure is quite challenging andcan take anywhere from forty-five minutes to two hours. The long-termsafety and efficacy of canaloplasty is very promising, but the procedureremains surgically challenging and invasive.

Another alternative is viscocanalostomy, which involves the injection ofa viscoelastic solution into Schlemm's canal to dilate the canal andassociated collector channels. Dilation of the canal and collectorchannels in this manner generally facilitates drainage of aqueous humorfrom the anterior chamber through the trabecular meshwork and Schlemm'scanal, and out through the natural trabeculocanalicular outflow pathway.Viscocanalostomy is similar to canaloplasty (both are invasive andab-externo), except that viscocanalostomy does not involve a suture anddoes not restore all 360 degrees of outflow facility. Some advantages ofviscocanalostomy are that sudden drops in intraocular pressure, hyphema,hypotony, and flat anterior chambers may be avoided. The risk ofcataract formation and infection may also be minimized because ofreduced intraocular manipulation and the absence of full eye wallpenetration, anterior chamber opening and shallowing, and iridectomy. Afurther advantage of viscocanalostomy is that the procedure restores thephysiologic outflow pathway, thus avoiding the need for externalfiltration, and its associated short and long term risks, in themajority of eyes. This makes the success of the procedure partlyindependent of conjunctival or episcleral scarring, which is a leadingcause of failure in traditional trabeculectomy procedures. Moreover, theabsence of an elevated filtering bleb avoids related ocular discomfortand potentially devastating ocular infections, and the procedure can becarried out in any quadrant of the outflow pathway.

However, current viscocanalostomy and canaloplasty techniques are stillvery invasive because access to Schlemm's canal must be created bymaking a deep incision into the sclera, creating a scleral flap, andun-roofing Schlemm's canal. In their current forms, these procedures areboth “ab-externo” procedures. “Ab-externo” generally means “from theoutside” and it is inherently more invasive given the location ofSchlemm's canal and the amount of tissue disruption required to accessit from the outside. On the other hand, “ab-interno” means “from theinside” and is a less invasive approach because of the reduced amount oftissue disruption required to access it from the inside. Consequently,an ab-interno approach to Schlemm's canal offers the surgeon easieraccess to the canal, but also reduces risk to the patient's eye andreduces patient morbidity. All of these lead to improved patientrecovery and rehabilitation. The ab-externo viscocanalostomy andcanaloplasty procedures also remain challenging to surgeons, because aspreviously stated, it is difficult to find and access Schlemm's canalfrom the outside using a deep incisional approach due to the smalldiameter of Schlemm's canal. A further drawback still is that at most,viscocanalostomy typically dilates up to 60 degrees of Schlemm's canal,which is a 360 degree ring-shaped outflow vessel-like structure. Themore of the canal that can be dilated, the more total aqueous outflowcan be restored.

Accordingly, it would be beneficial to have systems that easily andatraumatically provide access to Schlemm's canal using an ab-internoapproach for the delivery of ocular devices, tools, and compositions. Itwould also be useful to have systems that deliver devices, tools, andcompositions into Schlemm's canal expeditiously to decrease proceduretime and the risk of infection without compromising safety and precisionof the delivery procedure. It would also be useful to have systems thatdeliver devices, tools, and fluid compositions into Schlemm's canalusing an ab-interno approach so that cataract surgery and glaucomasurgery can both be accomplished during the same surgical sitting usingthe very same corneal or scleral incision. Such incisions are smallerand allow for less invasive surgery and more rapid patient recovery.This approach allows for accessing Schlemm's canal through thetrabecular meshwork from the inside of the eye, and thus it is called“ab-interno.” Methods of delivering ocular devices, tools, andcompositions that effectively disrupt the juxtacanalicular meshwork andadjacent wall of Schlemm's canal, also known as the inner wall ofSchlemm's canal, maintain the patency of Schlemm's canal, increaseoutflow, decrease resistance to outflow, or effectively dilate the canaland/or its collector channels using the systems in a minimally invasive,ab-interno manner would also be desirable.

BRIEF SUMMARY

Described here are systems and methods for easily and reliably accessingSchlemm's canal with minimal or reduced trauma and for delivering anocular device (e.g., an implant) therein. Other systems and methods maybe implant-free, and/or rely on the delivery and removal of atherapeutic (disruptive) tool and/or the delivery of a fluid compositioninto Schlemm's canal to improve flow through the trabeculocanalicularoutflow system, which consists of the trabecular meshwork,juxtacanalicular tissue, Schlemm's canal, and collector channels. Whenan ocular device is implanted, the ocular device may maintain thepatency of Schlemm's canal without substantially interfering withtransmural fluid flow across the canal. Transmural flow, or transmuralaqueous humor flow, is defined as flow of aqueous humor from theanterior chamber across the trabecular meshwork into the lumen ofSchlemm's canal, across and along the lumen of Schlemm's canal, andultimately into aqueous collector channels originating in the outer wallof Schlemm's canal. When a fluid composition is delivered into thecanal, the fluid composition, e.g., a viscoelastic fluid, delivered intothe canal may facilitate drainage of aqueous humor by dilating thecanal, rendering the trabecular meshwork and inner wall of Schlemm'scanal more permeable to aqueous humor, and also dilating aqueouscollector channels. When a therapeutic tool is delivered, the tool mayfacilitate drainage of aqueous humor by dilating the canal, dilating thecollector channels, disrupting or stretching the trabecular meshwork,disrupting or stretching the juxtacanalicular tissue, tearing or cuttingthe trabecular meshwork or juxtacanalicular tissue, or completelyremoving the trabecular meshwork or juxtacanalicular tissue. Any or allof these actions may reduce resistance to outflow, increase aqueousoutflow and drainage, and reduce intraocular pressure.

One of the beneficial features of the system may be a cannula configuredwith a distal curved portion that defines a radius of curvature, wherethe radius of curvature directly engages the bevel at the distal tip ofthe cannula. However, in some variations, the system may comprise astraight cannula. The specific configuration of the handle of the systemmay also be useful. The handle may be sized and shaped so that it iseasily manipulated with one hand. Furthermore, the handle may bedesigned for universal manipulation. By “universal” it is meant that thehandle is ergonomically configured for both right-handed and left-handeduse, for use to access any quadrant of the eye, and for use in advancinga cannula or elongate member into Schlemm's canal in a clockwise orcounterclockwise fashion. Such a configuration may include a driveassembly that can be easily actuated in a first orientation (e.g., todeliver an implant, tool, and/or fluid in a clockwise fashion) and thatcan be easily actuated in a second, flipped orientation (e.g., todeliver an implant, tool, and/or fluid in a counterclockwise fashion).Such a configuration may allow the drive assembly to be actuated usingeither a left hand or a right hand, and may allow the drive assembly tobe used with either the left eye or the right eye. Alternatively, insome variations the cannula itself can be rotated to the extent needed(e.g., 180 degrees) to provide ambidextrous ease of use in a clockwiseor counterclockwise advancement direction.

The ocular delivery systems described herein generally include auniversal handle having a grip portion and a housing that has aninterior and a distal end. A cannula is typically coupled to and extendsfrom the housing distal end. The cannula may include a proximal end anda distal curved portion, where the distal curved portion has a proximalend and a distal end, and a radius of curvature defined between theends. The cannula may also be configured to include a body; a distal tiphaving a bevel; and a lumen extending from the proximal end through thedistal tip. The bevel may directly engage the distal end of the curvedportion of the cannula (i.e., the bevel may directly engage the radiusof curvature). The systems may also generally include a drive assemblysubstantially contained within the housing comprising gears thattranslate rotational movement to linear movement.

When an ocular device is to be implanted into Schlemm's canal, thesystem may further include a slidable positioning element having aproximal end and a distal end that is coaxially disposed within thecannula lumen. The distal end of the slidable positioning element maycomprise an engagement mechanism for positioning (includingmanipulating) the ocular device within the canal. Exemplary engagementmechanisms that may be employed comprise hooks, jaws, clasps, forceps,or complimentary mating elements for releasable attachment of the oculardevices.

The system may be configured to include a fluid assembly in the handleand an elongate member comprising a lumen coaxially disposed within thecannula lumen when a fluid composition is to be delivered into Schlemm'scanal. The fluid composition may be delivered through the distal end ofthe lumen of elongate member or through openings spaced along the axiallength of the elongate member. Additionally, the fluid assembly may becoupled to a loading component configured to transfer fluid compositionsinto a reservoir at least partially defined by the assembly. Somevariations of the system may have the fluid composition preloaded in thereservoir. Exemplary fluid compositions include without limitation,saline, pharmaceutical compounds, and viscoelastic fluids. Theviscoelastic fluids may comprise hyaluronic acid, chondroitin sulfate,cellulose, or salts, derivatives, or mixtures thereof. Use of sodiumhyaluronate as the viscoelastic fluid may be beneficial. Some systemsmay be configured to deliver a therapeutic (disruptive) tool toSchlemm's canal, without the delivery of an implant or fluid. In thesevariations, the handle may or may not include a fluid reservoir, and thetool may have various configurations to disrupt tissue. An exemplarysystem may comprise an elongate member comprising an atraumatic distaltip configured to be advanced through Schlemm's canal, and configuredsuch that the body of the elongate member tears or cuts through thetrabecular meshwork when the system is removed from the eye.

Methods for implanting an ocular device within Schlemm's canal are alsodescribed. Using the ocular delivery systems disclosed herein, themethod generally includes the steps of creating an incision in theocular wall that provides access to the anterior chamber of the eye;advancing a cannula of the system through the incision, across a portionof the anterior chamber, to the trabecular meshwork, and piercing thetrabecular meshwork; accessing Schlemm's canal with the cannula; andimplanting the device within the canal. The cannula will typicallycomprise a proximal end and a distal curved portion, the distal curvedportion having a proximal end and a distal end and a radius of curvaturedefined between the ends; a body; a distal tip having a bevel, the beveldirectly engaging the distal end of the curved portion of the cannula;and a lumen extending from the proximal end through the distal tip. Apositioning element slidable within the cannula lumen may be employedduring the step of implanting the device within the canal. The devicemay be implanted to reduce intraocular pressure or to treat a medicalcondition such as glaucoma, pre-glaucoma, or ocular hypertension.

Methods for delivering a fluid composition into Schlemm's canal arefurther described. Using the ocular delivery systems disclosed herein,the method generally includes the steps of creating an incision in theocular wall that provides access to the anterior chamber of the eye;advancing a cannula of the system through the incision to the trabecularmeshwork; accessing Schlemm's canal with the cannula; and delivering thefluid composition into Schlemm's canal using a elongate membercomprising a lumen and slidable within the cannula lumen. The cannulawill typically comprise a proximal end and a distal curved portion, thedistal curved portion having a proximal end and a distal end and aradius of curvature defined between the ends; a body; a distal tiphaving a bevel, the bevel directly engaging the distal end of the curvedportion of the cannula; and a lumen extending from the proximal endthrough the distal tip. The fluid composition may be delivered intoSchlemm's canal through the distal end of the elongate member or throughopenings spaced along the axial length of the elongate member. Fluidssuch as saline and viscoelastic solutions may be delivered into thecanal to dilate the canal and collector channels and/or to disrupt thejuxtacanalicular meshwork or inner wall of Schlemm's canal to enhancepermeability to aqueous humor, reduce resistance to aqueous outflow, orincrease aqueous outflow. Examples of viscoelastic solutions are thosethat include hyaluronic acid, chondroitin sulfate, cellulose, andderivatives and mixtures thereof. As previously stated, the use ofsodium hyaluronate as the viscoelastic solution may be beneficial. Drugsfor treating glaucoma, steroids, anti-neovascularization (e.g.,anti-vascular endothelial growth factor (anti-VEGF) antibodies andderivatives), anti-inflammatory, or antifibrotic drugs may also becombined with the viscoelastic solutions. The drugs may also bedelivered alone without viscoelastic if desired.

When the fluid composition is delivered, the delivery step may includeactuation of the drive assembly so that retraction of at least a portionof the gears (or reversal of gear movement) pressurizes the reservoir inan amount sufficient to force the fluid composition through the lumen ofthe elongate member. The fluid composition may be delivered to dilateSchlemm's canal. The fluid composition may also be delivered to reduceintraocular pressure or to treat a medical condition such as glaucoma.

The systems, devices, and methods described herein may also employvarying degrees of force to disrupt trabeculocanalicular tissues, e.g.,the trabecular meshwork, juxtacanalicular tissue, Schlemm's canal, wallsof Schlemm's canal, septae, obstructions, or narrowings inside Schlemm'scanal, and collector channels, to improve drainage of aqueous humor andin turn, reduce intraocular pressure and treat conditions of the eye.The disruptive force may be generated by implant-free methods, e.g., bydelivering a disruptive volume of viscoelastic fluid which may expandthe canal and collector channels and may also stretch the trabecularmeshwork, advancing disruptive tools, e.g., cannulas, conduits,catheters, dilation probes, balloons, etc., which may or may not includeone or more disruptive components on their distal portions, or both.Depending on factors such as the type or severity of the condition beingtreated, the disruptive force may be generated to partially cut, tear,stretch, dilate, destroy, or completely destroy and/or remove, thetrabecular meshwork and/or juxtacanalicular tissue, and may be adjustedby varying the volume of viscoelastic fluid delivered, or by varying thetool configuration, as further discussed below.

The viscoelastic or aqueous fluid may be delivered using a unitary andsingle-handed, single-operator controlled system. Advancement of thedisruptive tools may also be provided by a unitary and single-handed,single-operator controlled system. By “unitary” it is meant that onesystem is employed to advance an elongate member through at least aportion of Schlemm's canal, and in some instances to also deliver aviscoelastic fluid, tool, or implant into Schlemm's canal. By“single-operator controlled” it is meant that all features of thesystem, e.g., cannula, elongate member, and tool advancement andretraction, ocular device delivery, fluid delivery, etc., can beperformed by one user. This is in contrast to other systems that useforceps to advance a delivery catheter into Schlemm's canal and/ordevices containing viscoelastic fluid that are separate or independentfrom a delivery catheter, and which require connection to the deliverycatheter during a procedure by an assistant or assistants while thedelivery catheter is held by the surgeon. Following delivery of adisruptive volume of fluid or a tool, an implant, e.g., a helicalsupport or scaffold, may be advanced into Schlemm's canal to maintainits patency, or energy delivered to modify the structure of Schlemm'scanal and/or the surrounding trabeculocanalicular tissues.

The single-handed, single-operator controlled system for deliveringfluids may include a cannula; an elongate member comprising a lumen andslidably disposed within, and advanceable distally from, the cannula;and a handle coupled to the cannula, where a portion of the handledefines a fluid reservoir, and where the handle is capable of beingoperated with a single-hand to deliver the fluid from the reservoirthrough the lumen of the elongate member.

Alternatively, a system for delivering viscoelastic fluids may include acannula; a elongate member comprising a lumen and slidably disposedwithin, and advanceable distally from, the cannula; a handle coupled tothe cannula, where a portion of the handle defines a fluid reservoir;and a linear gear moveable to advance a fluid from the fluid reservoirthrough the lumen of the elongate member.

The system for delivering viscoelastic fluids may also be configured toinclude a universal handle having a proximal end and a distal end; acannula extending from the distal end and having a proximal portion anda distal portion; a slidable elongate member comprising a lumen anddisposed within the cannula; a housing having an interior and upper andlower surfaces; and a wheeled drive assembly; where the wheeled driveassembly extends past the upper and lower surfaces of the housing. Sucha system having a universal handle may further include a rotatingcannula that can be rotated, e.g., from a left to right position, and awheeled drive assembly that comprises a single wheel (rotatablecomponent) configured to slide the elongate member. Instead of a wheel,a button, slide, foot pedal, or motorized mechanism could also beconfigured to slide the elongate member.

In all variations of the viscoelastic fluid delivery systems, theelongate member may comprise a lumen and may have an outer diameterranging from about 25 microns to about 1000 microns, from about 25microns to about 500 microns, from about 50 microns to about 500microns, from about 150 microns to about 500 microns, from about 200microns to about 500 microns, from about 300 microns to about 500microns, from about 200 microns to about 250 microns, or from about 180microns to about 300 microns. In some instances it may be beneficial forthe elongate member to have an outer diameter of about 240 microns. Theelongate member may also comprise a plurality of openings spaced alongat least a portion of its axial length or have a distal end with a cutout configured as a half tube.

In addition to disrupting Schlemm's canal and the surroundingtrabeculocanalicular tissues using a disruptive volume of viscoelasticfluid, the outer diameter of the elongate member may be sized to disruptthose tissues. For example, an elongate member having an outer diameterranging from about 200 microns to about 500 microns may be beneficialfor disrupting tissues. Furthermore, a distal portion of the elongatemember may include a disruptive component, e.g., a notch, hook, barb,balloon, or combinations thereof, that disrupts tissues. However, thesystems may not need to include both features, i.e., deliver adisruptive volume of viscoelastic fluid and also have a elongate membersized for disruption. An elongate member configured for disruption ofSchlemm's canal and surrounding tissues may be used alone to reduceintraocular pressure, without the delivery of fluids. Such an elongatemember may or may not have a lumen. In some variations, the elongatemember may be configured such that the body of the elongate member cutsor tears the trabecular meshwork as the system is removed from the eye.Elongate members may also be configured to comprise a balloon or beotherwise inflatable or expandable to a size that disrupts tissues as itis advanced.

The handle of the viscoelastic fluid delivery systems described hereinmay include a drive assembly capable of causing the fluid to bedelivered from the reservoir through the lumen of the elongate member.The drive assembly may be a wheeled drive assembly that includes onerotatable component or a plurality of rotatable components. Thereservoir may be preloaded with the viscoelastic fluid. Exemplaryviscoelastic fluids may comprise hyaluronic acid, chondroitin sulfate,cellulose, polymers, or salts, derivatives, or mixtures thereof. It maybe beneficial to use sodium hyaluronate as the viscoelastic fluid.

In some variations, the systems for introducing a fluid composition intoSchlemm's canal described here may comprise a housing, a cannula, aflexible elongate member, a reservoir, and a drive assembly. The cannulamay be attached to the distal end of the housing and may comprise adistal tip. The flexible elongate member may comprise a lumen and adistal end, and the distal end may be slidable within the cannulabetween a retracted position and an extended position. The distal endmay be within the cannula in the retracted positioned and distal to thedistal tip of the cannula in the extended position. The reservoir maycomprise a fluid composition and the reservoir may be fluidly connectedto the lumen of the flexible elongate member. The drive assembly may beconfigured to simultaneously move the flexible elongate member from theextended position to the retracted position and may deliver the fluidcomposition from the reservoir through the lumen of the flexibleelongate member. In some variations, the system may further comprise alock that may be configured to resist movement of the reservoir relativeto the housing. In some instances, the system may be configured toprevent movement of the flexible elongate member toward the extendedposition after the flexible elongate member has been retracted a fixedcumulative distance. In some of these instances, the fixed cumulativedistance may be about 40 mm.

In some instances, the drive assembly may comprise a linear gear. Thetranslation of the linear gear in a first direction may move theflexible elongate member toward the retracted configuration and maydeliver the fluid composition from the reservoir through the lumen ofthe elongate member. In some of these instances, translation of thelinear gear in a second direction may move the flexible elongate membertoward the extended configuration. The volume of fluid compositiondelivered from the reservoir may correspond to a distance of movement ofthe flexible polymeric elongate member toward the extendedconfiguration. In some variations, the drive assembly may furthercomprise a rotatable component and rotation of the rotatable componentmay cause translations of the linear gear. In some instances, the volumeof fluid composition delivered from the reservoir may correspond to adistance of translation of the linear gear in the first direction.

Also described here is a device for introducing a fluid composition intoSchlemm's canal. The device may comprise a housing, a reservoir, aflexible polymeric elongate member, and a drive assembly. The reservoirmay hold the fluid composition and may be located within the housing.The flexible polymeric elongate member may comprise a lumen fluidlyconnected to the reservoir. The drive assembly may be configured tocause a volume of fluid composition to be delivered from the reservoirto Schlemm's canal via the lumen of the flexible polymeric elongatemember and may cause the flexible polymeric elongate member to translateby a distance relative to the housing. The volume of fluid compositiondelivered may be fixed relative to the distance translated by theflexible elongate member. In some variations, the drive assembly maycomprise a rotatable wheel and the volume of fluid composition deliveredand the distance translated by the flexible polymeric elongate membermay be fixed relative to an amount of rotation of the wheel.

The implant-free methods for treating conditions of the eye may includeadvancing an elongate member into Schlemm's canal, where the elongatemember has been loaded with a volume of viscoelastic fluid, anddelivering the viscoelastic fluid into Schlemm's canal at a volumesufficient to disrupt the trabeculocanalicular tissues to reduceintraocular pressure. However, the implant-free methods for treatingconditions of the eye may not necessarily include delivery ofviscoelastic fluids. In these instances, the method may compriseadvancing an elongate member into Schlemm's canal, where the elongatemember has a diameter between about 200 and about 500 microns, and whereadvancement, retraction, or removal of the elongate member intoSchlemm's canal disrupts the trabeculocanalicular tissues sufficient toreduce intraocular pressure. In some instances, the method may compriseremoving the system from the eye, and in doing so cutting or tearingthrough the trabecular meshwork with the body of the elongate member.

Other methods for treating conditions of the eye may be single-handed,single-operator methods for introducing viscoelastic fluid intoSchlemm's canal that include advancing an elongate member into Schlemm'scanal, where the elongate member has been loaded with a volume ofviscoelastic fluid, and delivering the viscoelastic fluid into Schlemm'scanal, where delivering the volume of viscoelastic fluid is accomplishedby a single-handed system used by a single operator.

When viscoelastic fluids are delivered in the methods disclosed herein,the disruptive volume may be between about 2 μl (microliters) to about16 μl (microliters), or between about 2 μl to about 8 μl. In somevariations of the methods, the volume of fluid capable of disruptingtrabeculocanalicular tissues is about 2 μl, about 3 μl, about 4 μl,about 5 μl, about 6 μl, about 7 μl, about 8 μl, about 9 μl, about 10 μl,about 11 μl, about 12 μl, 13 μl, about 14 μl, about 15 μl, or about 16μl. It may be beneficial to deliver a volume of about 4 μl ofviscoelastic fluid in certain instances. In yet further variations, thevolume of fluid delivered ranges from about 1 μl per 360 degrees of thecanal to about 50 μl per 360 degrees of the canal. In yet furthervariations, the volume of fluid delivered ranges from about 0.5 μl per360 degrees of the canal to about 500 μl per 360 degrees of the canal.The viscoelastic fluid may be delivered while advancing the elongatemember of a single-handed, single-operator controlled system fromSchlemm's canal in the clockwise direction, counterclockwise direction,or both, and/or during withdrawal of the elongate member from Schlemm'scanal. The volume of viscoelastic fluid delivered may be fixed relativeto the distance traveled by the elongate member, and the viscoelasticfluid may be delivered to the same distance around Schlemm's canal asthe elongate member is advanced around the canal. As previously stated,the viscoelastic fluid may be delivered to disrupt Schlemm's canal andsurrounding trabeculocanalicular tissues. For example, the deliveredviscoelastic fluid may cause disruption by dilating Schlemm's canal,increasing the porosity of the trabecular meshwork, stretching thetrabecular meshwork, forming microtears or perforations injuxtacanalicular tissue, removing septae from Schlemm's canal, dilatingcollector channels, or a combination thereof. The elongate member may beloaded with the viscoelastic fluid at the start of an ocular procedureso that a single-operator can use a single hand to manipulate the system(e.g., advance and retract the elongate member or any associated tool)and deliver the fluid into the trabeculocanalicular tissues.

The methods disclosed herein may also include advancement of theelongate member about a 360 degree arc of Schlemm's canal, a 180 degreearc of Schlemm's canal, a 90 degree arc of Schlemm's canal, or otherdegree arc (e.g., between about a 5 degree arc and about a 360 degreearc). Advancement may occur from a single access point in Schlemm'scanal or from multiple access points in the canal. The disclosed methodsmay also be used to treat a variety of eye conditions, including, butnot limited to, glaucoma, pre-glaucoma, and ocular hypertension.

Methods for ab-interno trabeculotomy and goniotomy are also disclosedusing the system and steps disclosed herein, including advancing acannula at least partially through the anterior chamber of the eye,entering Schlemm's canal at a single access point using the cannula, anddelivering a volume of a viscoelastic fluid through a lumen of anelongate member slidable within, and extendable from, the cannula,sufficient to disrupt the structure of Schlemm's canal and surroundingtrabeculocanalicular tissues to reduce intraocular pressure. Anothermethod that may be useful in treating conditions of the eye includesentering Schlemm's canal using an elongate member extendable from asingle-operator controlled handle, the handle comprising a fluidreservoir, and delivering a volume of a viscoelastic fluid from thefluid reservoir through a lumen of the elongate member by increasingpressure within the fluid reservoir, where the volume of deliveredviscoelastic fluid is sufficient to disrupt the structure of Schlemm'scanal and surrounding tissues to reduce intraocular pressure. Othermethods for ab-interno trabeculotomy and goniotomy may include cutting,tearing, and/or removing trabecular meshwork without the delivery of aviscoelastic fluid. In such methods, an elongate member configured tomechanically tear or cut and remove trabecular meshwork may be employed.In some methods, the elongate member is configured to mechanically tearor cut the trabecular meshwork when the delivery system is removed fromthe eye after advancing the elongate member into Schlemm's canal. Inother methods, the elongate member may comprise a larger diameter,cutting features, and/or tool along or at the distal portion of theelongate member. For example, if the trabecular meshwork were being bothcut and removed, the conduit might pull excised tissue back into thecannula during retraction.

The methods for treating conditions of the eye described here maycomprise advancing an elongate member into Schlemm's canal andretracting the elongate member. The elongate member may comprise a lumenhaving a distal opening at a distal tip of the elongate member, andretracting the elongate member may include simultaneously delivering afluid composition out of the distal opening of the lumen. In somevariations, retracting the elongate member and delivering the fluidcomposition may both be actuated by rotation of a wheel. In someinstances, the elongate member may be advanced a first length aroundSchlemm's canal and the fluid composition may be delivered the samefirst length around Schlemm's canal. In some of the methods describedhere, the elongate member may be advanced about 180 degrees aroundSchlemm's canal in a first direction. Some of these methods may furthercomprise advancing the elongate member about 180 degrees aroundSchlemm's canal in a second direction, and retracting the elongatemember and simultaneously delivering a fluid composition out of thedistal opening of the lumen.

In some variations, the methods described here for delivering a fluidcomposition into Schlemm's canal using a device comprising a reservoir,a plunger comprising a lumen and a proximal end, and a flexible elongatemember comprising a lumen, with the reservoir fluidly connected to thelumen of the flexible elongate member via the lumen of the plunger andwith the proximal end of the plunger located slidably within thereservoir, may comprise moving the proximal end of the plungerproximally within the reservoir from an extended position to a depressedposition within the reservoir such that the plunger displaces fluidcomposition from the reservoir. The displaced fluid composition maytravel through the lumen of the plunger to the lumen of the flexibleelongate member.

In other variations, the methods described here for treating conditionsof the eye using a delivery system comprising a housing, a drivemechanism comprising a first wheel having a portion extending out of afirst side of the housing and a second wheel having a portion extendingout of a second side of the housing, a cannula extending form a distalend of the housing, and a slidable elongate member located slidablywithin the cannula, may comprise piercing trabecular meshwork of the eyewith the cannula, proximally moving the portion of the first wheelextending out of the first side of the housing to extend the slidableelongate member distally from a retracted position within the cannulasuch that it advances around Schlemm's canal in a first direction, anddistally moving the portion of the first wheel extending out of thefirst side of the housing to retract the slidable elongate memberproximally back to the retracted position. In some variations, distallymoving the portion of the first wheel extending out of the first side ofthe housing may also cause a fluid composition to be delivered intoSchlemm's canal. In some instances, the methods may further compriseproximally moving the portion of the second wheel extending out of thesecond side of the housing to extend the slidable elongate memberdistally from the retracted position within the cannula such that itadvances around Schlemm's canal in a second direction, and distallymoving the portion of the second wheel extending out of the second sideof the housing to cause the slidable elongate member to retractproximally back to the retracted position. In some instances, distallymoving the portion of the second wheel extending out of the second sideof the housing may also cause a fluid composition to be delivered toSchlemm's canal.

Methods for disrupting trabecular meshwork of an eye using a devicecomprising a cannula, a flexible tool slidable within the cannulabetween a retracted position within the cannula and an extendedposition, and a drive assembly, may comprise advancing the cannula intoan anterior chamber through a corneal or scleral incision, piercing thetrabecular meshwork of the eye with the cannula, extending the flexibletool from the retracted position to the extended position, andretracting the cannula from the anterior chamber without retracting theflexible tool. The drive assembly may be configured to advance theflexible tool a first maximum distance without being retracted and maybe configured to limit the cumulative advancement of the flexible toolto a maximum total distance. In some variations, the first maximumdistance may be between 15 mm and 25 mm, and the maximum total distancemay be between 35 mm and 45 mm.

In some variations, methods for disrupting trabecular meshwork of an eyeusing a device comprising a cannula, a flexible tool comprising a bodyand slidable within the cannula between a retracted position within thecannula and an extended position, may comprise advancing the cannulainto an anterior chamber through a corneal or scleral incision, piercingthe trabecular meshwork of the eye with a distal tip of the cannula,extending the flexible tool from the retracted position to the extendedposition, and tearing the trabecular meshwork with the body of theflexible tool progressively from a proximal end of the body to a distalend of the body.

The kits described here may comprise a first device and a second device.The first device may comprise a housing, a cannula, a flexible polymericelongate member, a reservoir, and a drive assembly. The cannula may beattached to the distal end of the housing and may comprise a distal tip.The flexible polymeric elongate member may comprise a lumen and a distalend, and the distal end may be slidable within the cannula between aretracted position and an extended position. The distal end may bewithin the cannula in the retracted positioned and distal to the distaltip of the cannula in the extended position. The reservoir may comprisea fluid composition and the reservoir may be fluidly connected to thelumen of the flexible polymeric elongate member. The drive assembly maybe configured to simultaneously move the flexible polymeric elongatemember from the extended position to the retracted position and maydeliver the fluid composition from the reservoir through the lumen ofthe flexible polymeric elongate member.

The second device may also comprise a housing, a cannula, a flexiblepolymeric elongate member, and a drive assembly. The cannula may beattached to the distal end of the housing and may comprise a distal tip.The flexible polymeric elongate member may comprise a lumen and a distalend. The distal end may be slidable within the cannula between aretracted position and an extended position and the distal end may bewithin the cannula in the retracted position and distal to the distaltip of the cannula in the extended position. The drive assembly may beconfigured to move the flexible polymeric elongate member from theextended position to the retracted position. The second device may notcomprise a reservoir.

In some variations, the kits described here may comprise a device and atray. The device may comprise a housing, a cannula, and a flexiblepolymeric elongate member. The cannula may be attached to the distal endof the housing and may comprise a distal tip. The flexible polymericelongate member may comprise a lumen and a distal end, and the distalend may be slidable within the cannula between a retracted position andan extended position. The distal end may be within the cannula in theretracted position and distal to the distal tip of the cannula in theextended position. The tray may be configured to removably receive thedevice. The tray may comprise a first set of pinch points and a secondset of pinch points and when the device is in the tray, the cannula maynot contact the tray.

In some instances, the device may further comprise a drive assembly andthe drive assembly may be configured to advance the flexible polymericelongate member a first maximum distance without being retracted. Thedevice may be configured to limit the cumulative advancement of theflexible polymeric elongate member to a maximum total distance. In someof these instances, the first maximum distance may be between 15 mm and25 mm and the maximum total distance may be between 35 mm and 45 mm.

As described here are methods of manufacturing a cannula for accessingSchlemm's canal. The methods may comprise creating a bevel at a distaltip of the cannula, sharpening the cannula, and smoothing a portion ofthe cannula. The distal tip of the cannula may comprise inner and outercircumferential edges and the cannula may comprise a lumen therethrough.The bevel may traverse the lumen and creating the bevel may createproximal and distal ends of the distal tip. Sharpening the cannula mayinclude sharpening the distal end of the distal tip of the cannulathereby creating a sharpened piercing tip. Smoothing a portion of thecannula may include smoothing a portion of the inner or outercircumferential edges. In some variations, the cannula may comprisestainless steel, Nitinol, or titanium hypodermic tubing.

In some variations, sharpening the distal end of the distal tip maycomprise grinding a portion of an external surface of the cannula and/ora portion of the outer circumferential edge. In some variations, thesharpened piercing tip may be configured to pierce trabecular meshworkof an eye. In some instances, the sharpened piercing tip may comprisetwo angled surfaces. In some of these instances, an angle between thetwo angled surfaces may be between 50 degrees and 100 degrees.

In some instances, smoothing a portion of the inner or outercircumferential edges may comprise smoothing the inner circumferentialedge at the proximal end of the distal tip. In some variations,smoothing a portion of the inner or outer circumferential edges maycomprise smoothing the outer circumferential edge at the proximal end ofthe distal tip. In some instances, smoothing a portion of the inner orouter circumferential edges may comprise smoothing both the inner andouter circumferential edges at the proximal end of the distal tip. Insome variations, smoothing a portion of the inner or outercircumferential edges may comprise smoothing the inner circumferentialedge at the distal end of the distal tip. In some instances, smoothing aportion of the inner or outer circumferential edges may comprisesmoothing the entire inner circumferential edge and smoothing the outercircumferential edges at the proximal end of the distal tip. In any ofthese variations or instances, smoothing may comprise abrasivelyblasting with a soda media.

In some variations, the methods of manufacturing may further compriseapplying a protective covering to the sharpened piercing tip prior tothe smoothing step. In these variations, the sharpened piercing tip maycomprise angled surfaces and the angles surfaces may be covered by theprotective covering.

In some instances, the methods of manufacturing may further comprisepolishing the distal tip. In some of these instances, polishing maycomprise electropolishing. In some variations, the methods may furthercomprise passivating the cannula. In some of these variations,passivating may remove iron oxide from the cannula. Additionally, insome of these variations, passivating may comprise passivating withacid. In some instances, the methods may further comprise roughening atleast a portion of the cannula proximal to the distal tip. In some ofthese instances, roughening may comprise abrasively blasting with a sodamedia.

In variations of the methods of manufacturing described here the methodsmay further comprise cutting the cannula to a length between 50 mm and70 mm. In some of these variations, cutting the cannula may comprisecutting the cannula to a length of 60 mm.

In some instances, the methods of manufacturing may further comprisebending a distal portion of the cannula along a longitudinal axis of thecannula. In some of these instances, bending a distal portion of thecannula may comprise bending the distal portion to an angle between 100degrees and 125 degrees. In some of these instances, bending the distalportion of the cannula may comprise bending the distal portion to a 118degree angle.

In some variations, the methods of manufacturing a cannula for accessingSchlemm's canal may comprise cutting a cannula to a working length,roughening an outer surface of the cannula, creating a bevel at a distaltip of the cannula, grinding the distal end of the distal tip, applyinga protective covering, smoothing a portion of the cannula, bending thecannula, electropolishing the cannula, and passivating the cannula. Insome variations, the cannula may comprise a proximal portion, a centralportion, a distal portion, and a lumen therethrough and the distalportion may comprise a distal tip. In some instances, toughening anouter surface of the cannula may include roughening an outer surface ofthe central portion of the cannula. In some variations, the distal tipof the cannula may comprise inner and outer circumferential edges, andthe cannula may comprise a lumen therethrough. In some instances, thebevel may traverse the lumen and creating the bevel may create proximaland distal ends of the distal tip. In some variations, grinding thedistal end of the distal tip may thereby further sharpen the distal endof the distal tip to create a sharpened piercing tip. In some instances,applying a protective covering may include applying a protectivecovering to the sharpened piercing tip and smoothing a portion of thecannula may include smoothing a portion of the inner or outercircumferential edge. In some variations, bending the cannula mayinclude bending the distal portion of the cannula along a longitudinalaxis of the cannula and electropolishing the cannula may includeelectropolishing the distal tip. In some instances, passivating thecannula may include passivating the cannula with acid.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a stylized, cross-sectional view of the eye and some of thestructures involved in the flow of aqueous humor out of the eye.

FIG. 2 depicts a perspective view of an exemplary delivery system forimplanting an ocular device.

FIG. 3 depicts a side view of an exemplary cannula of the deliverysystem.

FIGS. 4A-4B depict perspective views of an exemplary drive assembly.FIG. 4A shows the drive assembly in the handle of the system in a firstorientation and FIG. 4B shows the handle in a second, flippedorientation.

FIGS. 5A-5B show perspective views of an exemplary engagement mechanismfor delivery of an illustrative ocular implant.

FIG. 6 shows a perspective view of an engagement mechanism for deliveryof an illustrative ocular implant according to one variation.

FIGS. 7A-7B show perspective views of engagement mechanisms for deliveryof an illustrative ocular implant according to other variations.

FIG. 8A-8B depict perspective views of an engagement mechanism fordelivery of an illustrative ocular implant according to yet a furthervariation.

FIG. 9 depicts a perspective view of another exemplary engagementmechanism for delivery of an illustrative ocular implant.

FIGS. 10A-10B show an exemplary delivery system for delivering a fluidcomposition into Schlemm's canal. FIG. 10A is a perspective view of thesystem. FIG. 10B is a partial cross-sectional view of the system.

FIGS. 11A-11C illustrate an exemplary method of delivering a fluidcomposition out of the delivery system.

FIG. 12 depicts an exemplary slidable elongate member for delivering afluid composition.

FIGS. 13A-13C show side or perspective views of slidable elongatemembers according to other variations.

FIG. 14 is a stylized depiction of an ab-interno method for accessingSchlemm's canal with the cannula of an exemplary delivery system.

FIG. 15 depicts an exemplary cannula according to another variation.

FIG. 16 is a stylized depiction of an ab-interno method of accessingSchlemm's canal from a single point, and delivering a viscoelastic fluidwhile advancing a fluid delivery elongate member along a 360 degree arcof the canal.

FIG. 17 is a stylized depiction of an ab-interno method of accessingSchlemm's canal from a single point, and delivering a viscoelastic fluidwhile advancing a fluid delivery elongate member in both the clockwiseand counterclockwise directions along a 180 degree arc of the canal.

FIGS. 18A-18C illustrate an exemplary ab-interno method of cutting ortearing the trabecular meshwork.

FIG. 19 is a flow-chart illustrating an exemplary manufacturing methodfor a cannula that may be used with the devices, systems, and methodsdescribed here.

FIG. 20 is a perspective view of a variation of a distal tip of acannula.

FIGS. 21A and 21B are perspective and front views, respectively, of avariation of a distal tip of a cannula.

FIGS. 22A-22B depict perspective views of an exemplary drive assembly ofa delivery system. FIG. 22C shows a perspective view of the deliverysystem with an extended slidable elongate member. FIG. 22D shows aperspective view of the delivery system without a top portion of thehousing with an extended slidable elongate member.

FIG. 23A shows a perspective view of an exemplary delivery system fordelivering a fluid.

FIG. 23B shows a cutaway view of the delivery system of FIG. 23A. FIGS.23C-23D show perspective views of the delivery system of FIG. 23Awithout the housing. FIG. 23E shows a close-up cutaway view of theproximal end of the delivery system of FIG. 23A. FIG. 23F shows aperspective view of the delivery system of FIG. 23A without a topportion of the housing with an extended slidable elongate member.

FIG. 24 depicts a perspective view of another exemplary delivery systemfor delivering a fluid.

FIGS. 25A-25B depict perspective views of an exemplary delivery systemwith a lock removed (FIG. 25A) and inserted (25B) into the handle. FIGS.25C-25D show perspective and cutaway views, respectively, of the lockrotated to allow loading of the reservoir.

FIGS. 26A-26B show perspective views of an exemplary tray for a deliverysystem with a delivery system (FIG. 26A) and with a delivery system andloading tool (FIG. 26B). FIG. 26C shows an exploded view of an exemplarypackaged kit.

FIGS. 27A-27B show exemplary kits comprising multiple delivery systems.

FIG. 28A is a flow-chart illustrating an exemplary method for deliveringa fluid to Schlemm's canal. FIGS. 28B-D depict delivery of fluid as aslidable elongate member is retracted as part of the method of FIG. 28A.

FIG. 29A is a flow-chart illustrating an exemplary method for disruptingtrabecular meshwork. FIGS. 29B-D depict disruption of the trabecularmeshwork as part of the method of FIG. 29A.

DETAILED DESCRIPTION

Described here are systems and methods for accessing Schlemm's canal andfor delivering an ocular device, tool, and/or fluid composition thereinto reduce intraocular pressure and thereby treat conditions of the eye.The fluids and certain components of the system, e.g., the slidableelongate member, may be used to provide a force for disruptingtrabeculocanalicular tissues, which include the trabecular meshwork,juxtacanalicular tissue, Schlemm's canal, and the collector channels. Asused herein, the term “disrupting” refers to the delivery of a volume offluid or a system component that alters the tissue in a manner thatimproves flow through the trabeculocanalicular outflow pathway. Examplesof tissue disruption include, but are not limited to, dilation ofSchlemm's canal, dilation of collector channels, increasing the porosityof the trabecular meshwork, stretching the trabecular meshwork, formingmicrotears or perforations in juxtacanalicular tissue, removing septaefrom Schlemm's canal, cutting, tearing, or removal oftrabeculocanalicular tissues, or a combination thereof.

To better understand the systems and methods described here, it may beuseful to explain some of the basic eye anatomy. FIG. 1 is a stylizeddepiction of a normal human eye. The anterior chamber (100) is shown asbounded on its anterior surface by the cornea (102). The cornea (102) isconnected on its periphery to the sclera (104), which is a tough fibroustissue forming the protective white shell of the eye. Trabecularmeshwork (106) is located on the outer periphery of the anterior chamber(100). The trabecular meshwork (106) extends 360 degreescircumferentially around the anterior chamber (100). Located on theouter peripheral surface of the trabecular meshwork (106) is Schlemm'scanal (108). Schlemm's canal (108) extends 360 degrees circumferentiallyaround the meshwork (106). At the apex formed between the iris (110),meshwork (106), and sclera (104), is the anterior chamber angle (112).

The systems are generally configured for single-handed manipulation andfor control by a single operator, and include one or more featuresuseful for easily accessing Schlemm's canal with minimal trauma. Onceaccess to the canal has been obtained, the system may deliver an oculardevice, a tool, and/or a fluid composition. In some variations, thesystem advances a tool that disrupts Schlemm's canal and surroundingtissues without delivery of an ocular device or a fluid composition. Forexample, the tool may be an elongate member, slidable within, andextendable from, the cannula used to access the canal, having an outerdiameter sized to disrupt the canal and surrounding tissues. The body ofthe elongate member may be in some instances configured to cut or tearthrough the trabecular meshwork if the system is removed from the eyewhile the elongate member is within Schlemm's canal, and/or the distalend of the elongate member may be provided with a disruptive componentto aid in the disruption of trabeculocanalicular tissues.

When a device is implanted into the canal, it will generally beconfigured to maintain the patency of Schlemm's canal withoutsubstantially interfering with transmural fluid flow across the canal.This may restore, enable, or enhance normal physiologic efflux ofaqueous humor through the trabeculocanalicular tissues. Ocular implantssuch as those disclosed in U.S. Pat. No. 7,909,789, and such as thosedisclosed in U.S. Pat. No. 8,529,622, each of which is herebyincorporated by reference in its entirety, may be delivered. In somevariations, the implants in U.S. Pat. Nos. 7,909,789 and 8,529,622include a support having a least one fenestration that completelytraverses a central core of Schlemm's canal without substantiallyinterfering with transmural fluid flow or longitudinal fluid flow acrossor along the canal. The ocular device may also disrupt thejuxtacanalicular trabecular meshwork or adjacent inner wall of Schlemm'scanal. The ocular devices may also be coated with a drug useful fortreating ocular hypertension, glaucoma, or pre-glaucoma, infection, orscarring, neovascularization, fibrosis, or inflammation postoperatively.The ocular device may also be formed to be solid, semi-solid, orbioabsorbable.

The systems may also be used to deliver a fluid composition, e.g.,saline or a viscoelastic fluid. The saline may be used for irrigation.The viscoelastic fluid may be employed in ab-interno versions ofviscocanalostomy or canaloplasty procedures to disrupt the canal andsurrounding tissues.

I. Systems/Devices

The systems described herein may be single-handed, single-operatorcontrolled devices that generally include a universal handle having agrip portion and a housing that has an interior and a distal end. Acannula is typically coupled to and extends from the housing distal end.The cannula may include a proximal end and a distal curved portion,where the distal curved portion has a proximal end and a distal end, anda radius of curvature defined between the ends. In other variations, thecannula may be straight and may not comprise a distal curved portion.The cannula may also be configured to include a body; a distal tiphaving a bevel; and a lumen extending from the proximal end through thedistal tip. The bevel may directly engage the distal end of the curvedportion of the cannula (i.e., the bevel may directly engage the radiusof curvature). The systems may also generally include a drive assemblypartially contained within the housing comprising gears that translaterotational movement to linear movement. When an ocular device is to beimplanted into Schlemm's canal, the systems may further include aslidable positioning element having a proximal end and a distal end thatis coaxially disposed within the cannula lumen. The system may also beconfigured to include a slidable elongate member comprising a lumen thatis coaxially disposed within the cannula lumen. When a fluid compositionis to be delivered into Schlemm's canal, the system may also beconfigured to include a fluid assembly in the handle. Fluid compositionssuch as saline, viscoelastic fluids, including viscoelastic solutions,air, and gas may be delivered using the system. Suitable markings,colorings, or indicators may be included on any portion of the system tohelp identify the location or position of the distal end of the cannula,the positioning element, the engagement mechanism, the ocular device, orthe slidable elongate member. In some instances, the systems describedherein may be used to perform ab-interno trabeculotomy, ab-internotransluminal trabeculotomy, clear corneal trabeculotomy, clear cornealtransluminal trabeculotomy, ab-interno canaloplasty, and/or clearcorneal canaloplasty, and may be used to deliver a fluid compositioninto the anterior or posterior segment of the eye.

An exemplary ocular delivery system is depicted in FIG. 2. In thefigure, delivery system (200) includes a universal handle (202) having agrip portion (204) and a housing (206). The housing has a proximal end(208) and a distal end (210). A cannula (212) is coupled to and extendsfrom the housing distal end (210). A drive assembly (214) issubstantially contained within the housing (206) that actuates movementof a positioning element (not shown). Port (216) is provided on thedistal end of the housing (210) for removable connection to a source ofirrigation fluid.

The delivery systems described herein may in some variations be fullydisposable. In other variations, a portion of the delivery system may bereusable (e.g., non-patient contact materials, such as the handle),while a portion of the delivery system may be disposable (e.g.,patient-contact materials, such as the cannula and elongate member). Inyet other variations, the delivery systems described herein may be fullyreusable.

Universal Handle

The ocular delivery systems described herein may include a universalhandle capable of single-handed use. For example, the handle may beconfigured to be capable for use with the left or right hand, for use onthe left or right eye, or in the clockwise or counterclockwisedirection. That is, the handle may be configured such that the abilityto use the delivery system is independent of which hand is used, whicheye a procedure is performed on, or which direction around the canal anocular device, tool, or fluid composition is delivered. For example, thedelivery system may be used to deliver an ocular device, elongatemember, and/or fluid composition in a clockwise direction in an eye, andthen with a simple flip of the handle (or by rotating the cannula itself180 degrees in another variation) to a second orientation, may be usedto deliver an ocular device, elongate member, and/or fluid compositionin the counterclockwise direction. However, it should be appreciatedthat in other variations, the delivery systems described herein may beconfigured to be used in a particular configuration (e.g., with a singleside up, only in a clockwise direction, only in a counterclockwisedirection, etc.). The handle generally includes a grip portion and ahousing. The grip portion may be raised, depressed, or grooved incertain areas, or textured to improve hold of the handle by the user orto improve comfort of the user. The housing may include an interiorportion and a distal end. The interior portion of the housing maycontain a drive assembly and a positioning element (both furtherdescribed below). In some variations, the distal end of the housingincludes a fluid port that can provide fluids for irrigation of theoperative field or to purge air from the system.

The universal handle may be made from any suitable material, includingwithout limitation, fluoropolymers; thermoplastics such aspolyetheretherketone, polyethylene, polyethylene terephthalate,polyurethane, nylon, and the like; and silicone. In some variations, thehousing or portions thereof may be made from transparent materials.Materials with suitable transparency are typically polymers such asacrylic copolymers, acrylonitrile butadiene styrene (ABS),polycarbonate, polystyrene, polyvinyl chloride (PVC), polyethyleneterephthalate glycol (PETG), and styrene acrylonitrile (SAN). Acryliccopolymers that may be particular useful include, but are not limitedto, polymethyl methacrylate (PMMA) copolymer and styrene methylmethacrylate (SMMA) copolymer (e.g., Zylar 631® acrylic copolymer). Invariations in which the universal handle is reusable, the handle may bemade from a material that can be sterilized (e.g., via autoclaving),such as a heat-resistant metal (e.g., stainless steel, aluminum,titanium).

The length of the universal handle may generally be between about 1 inch(2.5 cm) to about 20 inches (50.8 cm). In some variations, the length ofthe universal handle may be between about 4 inches (10.2 cm) and 10inches (25.4 cm). In some variations, the length of the universal handleis about 7 inches (17.8 cm).

Cannula

The cannula of the ocular delivery system is typically coupled to andextends from the housing distal end, and is generally configured toprovide easy and minimally traumatic access to Schlemm's canal using aminimally invasive ab-interno approach. The cannula may be fixedlyattached to the distal end of the housing, or in other variations it maybe rotatably attached to the distal end of the housing. In variations ofthe delivery systems where the handle is reusable and the cannula isdisposable, the cannula may be removably attached to the distal end ofthe housing. Some variations of the cannula may include a proximal endand a distal curved portion, where the distal curved portion has aproximal end and a distal end, and a radius of curvature defined betweenthe ends. However, it should be appreciated that in other variations thecannula may be straight and may not comprise a distal curved portion.The cannula may also be configured to include a body; a distal tiphaving a bevel and a sharpened piercing tip; and a lumen extending fromthe proximal end through the distal tip. When the cannula comprises adistal curved portion, the bevel may directly engage the distal end ofthe curved portion of the cannula (i.e., the bevel may directly engagethe radius of curvature). In some variations, the sharpened piercing tipmay comprise one or more angled surfaces, as is described in more detailbelow.

The cannula may be made from any suitable material with sufficientstiffness to allow it to be advanced through the eye wall and anteriorchamber. For example, the cannula may be formed of a metal such asstainless steel, nickel, titanium, aluminum, or alloys thereof (e.g.,Nitinol metal alloy), a polymer, or a composite. Exemplary polymersinclude without limitation, polycarbonate, polyetheretherketone (PEEK),polyethylene, polypropylene, polyimide, polyamide, polysulfone,polyether block amide (PEBAX), and fluoropolymers. In some instances, itmay be advantageous to coat the cannula with a lubricious polymer toreduce friction between the ocular tissue and the cannula during theprocedure. Lubricious polymers are well known in the art, and include,without limitation, polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone, fluorinated polymers (including polytetrafluoroethylene(PTFE or Teflon®)), and polyethylene oxide. In variations in which thecannula is reusable, the cannula may be made from a material that can besterilized (e.g., via autoclaving), such as a heat-resistant metal(e.g., stainless steel, aluminum, titanium).

The cannula generally has an outer diameter sized to gain access to thelumen of Schlemm's canal while minimally obstructing the surgeon's view.Accordingly, the outer diameter may range from about 50 microns to about1000 microns. In some variations, the outer diameter may range fromabout 150 microns to about 800 microns. The cannula also has an innerdiameter, which may range from about 50 microns to about 400 microns.The cannula may also be formed to have any suitable cross-sectionalprofile, e.g., circular, elliptical, triangular, square, rectangular,etc.

The cannula may be configured to include multiple portions or parts. Acannula having a body, a distal curved portion having a proximal end anda distal end, a radius of curvature defined between the ends, and abevel at the distal tip of the cannula that directly engages the distalend of the curved portion of the cannula may be particularly useful foraccessing the lumen of Schlemm's canal. Here the body (straight portionof the cannula) may have a length ranging from about 5 mm to about 50mm, about 10 mm to about 30 mm, or from about 14 mm to about 20 mm. Insome variations, the body may have a length of about 18 mm. The distalcurved portion of the cannula may be uniform in cross-sectional shape orit may taper closer to the distal end to facilitate entry into Schlemm'scanal. The radius of curvature of the distal curved portion may beadapted to facilitate tangential entry, as well as precise and minimallytraumatic entry into Schlemm's canal, and may range from about 1 mm toabout 10 mm or from about 2 mm to about 5 mm. In one variation, theradius of curvature is about 2.5 mm. The cannula may also have anangular span suitable for facilitating entry into Schlemm's canal, andmay range from about 70 degrees to about 170 degrees, or about 100degrees to about 150 degrees. In one variation, the angular span isabout 120 degrees.

The size, shape, geometry, and the like, of the bevel at the distal endof the curved portion of the cannula may be beneficial in allowing easyand minimally traumatic access to Schlemm's canal. In this respect, andas described in further detail below, having a bevel that directlyengages the radius of curvature of the distal end of the cannula may beparticularly useful.

In other variations, the cannula may include a short straight segmentcoupled to the distal end of the distal curved portion of the cannula(e.g., at the end of the radius of curvature). Here the bevel engagesthe straight segment and not the radius of curvature. The length of thestraight segment may range from about 0.5 mm to about 5 mm. In somevariations, the length of the straight segment ranges from about 0.5 mmto about 3 mm, or from about 0.5 mm to about 1 mm. The length of thestraight segment may also be less than about 0.5 mm, e.g., it may beabout 0.1 mm, about 0.2 mm, about 0.3 mm, or about 0.4 mm. In variationswhere the bevel directly engages the distal end of the curved portion ofthe cannula (i.e., the bevel directly engages the radius of curvature),the cannula lacks a straight segment (length of the straight segment iszero).

It may also be useful to have a bevel that is sharp and short tominimize the distance that any ocular device will have to travel whenbeing implanted into the canal. Exemplary bevel angles may range fromabout 10 degrees to about 90 degrees. In some instances, the bevel anglemay range from about 10 degrees to about 50 degrees. In one variation,the bevel angle is about 35 degrees, while in another variation thebevel is about 25 degrees. The bevel may also be oriented in anysuitable direction. For example, the bevel may be oriented so that itopens up towards the surgeon, or it may be reversed to open away fromthe surgeon or in any plane in between.

As is described in more detail below, in yet some variations, thecannula is configured to include one section that is sharp, and anothersection that is blunt (e.g., deburred). The dual surface configurationof such a cannula may be advantageous, since it may provide easier canalaccess by piercing the meshwork while also providing a gentle, dispersedforce on the elongate member during elongate member retraction into thecannula to avoid cutting or breaking the elongate member due toretraction force. For example, as shown in FIG. 15, the distal end ofcannula (1500) may have a sharpened piercing tip (1502) and a smoothedge (1504) that define portions of opening (1506), through which aslidable elongate member (not shown) may be advanced and retracted. Asis described in more detail with respect to FIGS. 19, 20A-20B, and 21,the sharp tip (1502) may be formed by compounding multiple bevels, andthe smooth edge (1504) may be created by smoothing or deburring innerand/or outer circumferential edges of the distal tip. Additionally, insome embodiments, the internal and/or external surfaces of the elongatemember adjacent to the opening (1506) may also be smoothed. Methods ofmaking the cannula are described in more detail below.

The cannula of an exemplary delivery system is shown in more detail inFIG. 3. Here the cannula (300) comprises a proximal end (302) a distalcurved portion (304), a body (314), and a distal tip (306). The distalcurved portion (304) has a proximal end (308) and a distal end (310),and a radius of curvature (R) that is defined between the ends (308,310). The distal curved portion (304) also has an inner radius (320)defined by the surface of the cannula closest to the center of theradius of curvature (R), and an outer radius (322) defined by thesurface of cannula further away from the center. A bevel (312) at thedistal tip (306) directly engages the distal end of the curved portionof the cannula (310). In other words, the bevel (312) may be contiguouswith the distal end of the curved portion of the cannula (310). Aspreviously stated, this configuration of the distal curved portion (304)and bevel (312) may be beneficial or advantageous for allowing easy,atraumatic, and controlled access into Schlemm's canal. The angle of thebevel may also be important. In general, a short bevel may bebeneficial. The bevel (312) may comprise an angle (A) between about 5degrees and about 85 degrees. In some variations, the angle (A) may beabout 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, or85 degrees. In some variations, the angle (A) may be between about 23degrees and about 27 degrees. In the variation shown in FIG. 3, thebevel angle (A) is about 25 degrees.

FIG. 20 depicts a perspective view of a distal tip (2002) of a cannula(2000) comprising a bevel (2014). The distal tip (2002) may be cut orground at an angle to create the bevel (2014). As shown, the beveleddistal tip (2002) comprises a proximal end (2008), a distal end (2010),and an elongated opening (2012) having an elliptical, rather than acircular, shape. The distal tip (2002) may comprise an elliptical shapedlumen opening that is angled such that the top of the elliptical openingis closer to the proximal portion of the cannula than the bottom of theelliptical opening. Also shown in FIG. 20 are inner and outercircumferential edges (2004, 2006).

FIGS. 21A and 21B depict perspective and front views, respectively, of avariation of a distal tip (2100) of a cannula comprising a bevel (2102)and a sharpened piercing tip (2114). As shown there, the distal tip(2100) also comprises a proximal end (2108), a distal end (2110), innerand outer circumferential edges (2104, 2106), and a lumen opening(2112). The sharpened piercing tip (2114) may comprise two angledsurfaces (2116) that converge to form a sharp point. The angled surfaces(2116) may have any suitable angle that results in a sharpened piercingtip (2114). For example, in some instances, the angle surfaces (2116)may have an angle (B) relative to the longitudinal axis of the distaltip (2100) of about 20, 25, 30, 35, 40, 45, or 50 degrees, between about25 and about 50 degrees, or between about 37.5 and about 42.5 degrees.In some instances, the angle (B) may be about 40 degrees. Accordingly,in some variations, the angle between the two angled surfaces (2116) maybe between about 50 and about 100 degrees, and in some instances, theangle between the two angled surfaces (2116) may be about 80 degrees. Itshould be appreciated that although the distal tip (2100) is depictedwith two angled surfaces, a distal tip with a single angled surface mayalso be used.

Elongate Member

The delivery systems described herein may comprise a slidable elongatemember coaxially disposed within the cannula lumen. The elongate memberemployed with the systems described herein may be of variousconfigurations, and may or may not comprise a lumen. The elongate membermay or may not be configured to deliver a fluid composition.

The elongate member may be coaxially disposed and slidable within thecannula lumen of the delivery systems described here. When the elongatemember is in a retracted position relative to the cannula, the distalend of the elongate member may be located within (i.e., proximal to) thedistal tip of the cannula. When the elongate member is in an extendedposition relative to the cannula, the distal end of the elongate membermay be located outside of (i.e., distal to) the distal tip of thecannula. The length of extension of the elongate member beyond thedistal tip of the cannula may correspond to the distance aroundSchlemm's canal that may be traversed by the elongate member (e.g., inorder to disrupt Schlemm's canal and/or surrounding trabeculocanaliculartissues, and/or to deliver a fluid composition). In variations in whichthe delivery system is configured to deliver a fluid composition, thelength traversed by the elongate member may correspond to the lengtharound Schlemm's canal to which the fluid composition is delivered. Invariations in which the delivery system is configured to tear or cut thetrabecular meshwork, the length traversed by the elongate member maycorrespond to the length of trabecular meshwork that is cut or torn. Insome variations, this length may be between about 1 mm and about 50 mm.In some of these variations, the length may be between about 10 mm andabout 40 mm, between about 15 mm and about 25 mm, between about 16 mmand about 20 mm, between about 18 mm and about 20 mm, between about 19mm and about 20 mm, between about 18 mm and about 22 mm, about 20 mm,between about 30 mm and about 50 mm, between about 35 mm and about 45mm, between about 38 mm and about 40 mm, between about 39 mm and about40 mm, or about 40 mm. The elongate member may be moved between extendedand retracted positions using a drive assembly of the delivery system,described in more detail below.

The elongate member may be sized so that it can be advanced through thecannula and into a portion of Schlemm's canal (e.g., 0 to 360 degrees ofthe canal) to disrupt trabeculocanalicular tissues, stent, and/or applytension to the canal, and/or to deliver a fluid composition. Theelongate member may be made from any suitable material that imparts thedesired flexibility and pushability for introduction through the eyewall, accessing Schlemm's canal, and/or navigation through other oculartissue structures. For example, the elongate member may comprise apolymer (e.g., nylon, polypropylene); a polymer reinforced with metalwire, braid or coil; composites of polymers and metal; or metals such asstainless steel, titanium, shape-memory alloy (e.g., Nitinol), or alloysthereof. In variations in which the elongate member is reusable, theelongate member may be made from a material that can be sterilized(e.g., via autoclaving), such as a heat resistant metal (e.g., stainlesssteel, aluminum, titanium). The elongate member may be straight withenough flexibility and pushability to navigate the ring-shaped Schlemm'scanal or may be pre-shaped to about a 2-10 mm radius of curvature orabout a 6 mm radius of curvature (i.e., the approximate radius ofcurvature of Schlemm's canal in an adult human) to more easilycircumnavigate Schlemm's canal, partially or in its entirety. In somevariations, the elongate member may be configured to be advanced over oralong a guidewire.

It may in some variations be desirable for the elongate member to haveone or more features to improve visualization of the elongate member.For example, the elongate member may be colored (e.g., red, orange,yellow, green, blue, purple, etc.). Additionally or alternatively,visualization may be improved using an illuminated beacon, a fiberoptic, side illuminating fiber optic, luminescence, fluorescence, or thelike. For example, a fiber optic may travel along the body of theelongate member to deliver light to the distal tip of the elongatemember, which may improve visualization of the distal tip of theelongate member as it is advanced or retracted about Schlemm's canal.

In some variations, the elongate member may be sized to have an outerdiameter sufficient to disrupt Schlemm's canal and surroundingtrabeculocanalicular tissues. The outer diameter may range from about 25microns to about 1000 microns, from about 25 microns to about 500microns, from about 50 microns to about 500 microns, from about 150microns to about 500 microns, from about 200 microns to about 500microns, from about 300 microns to about 500 microns, from about 200microns to about 250 microns, from about 150 microns to about 200microns, or from about 180 microns to about 300 microns. In someinstances it may be beneficial for the elongate member to have an outerdiameter of about 240 microns.

In some variations, the distal end of the elongate member may beconfigured as a blunt bevel, an atraumatic tip, an enlarged atraumatictip, or the like, to help the elongate member be advanced throughSchlemm's canal. In some of these variations, the distal end maycomprise a blunt parasol-shaped atraumatic tip. In other variations, adistal portion of the elongate member may optionally include adisruptive component, e.g., a notch, hook, barb, a rough surface, orcombination thereof, to disrupt the juxtatrabecular portion of Schlemm'scanal or juxtatrabecular meshwork. One or more projections emanatingfrom the elongate member may further disrupt the juxtatrabecular portionof Schlemm's canal or juxtatrabecular meshwork and thus increasepermeability of aqueous humor through the trabecular meshwork intoSchlemm's canal. In some instances, the elongate member may also deliverenergy to the trabeculocanalicular tissues (e.g., ultrasonic energy,radiofrequency energy (e.g., for electrocautery, electroablation),electromagnetic radiation, light energy (e.g., via a fiber optic)).

In some instances, the elongate member may comprise a filament (e.g., afilament comprising nylon, polypropylene, metal, or the like). Forexample, the elongate member may comprise a nylon monofilament. Anexemplary range of filament size may range from about 50 microns toabout 300 microns. The filament may be configured to be advanced throughall or a portion of Schlemm's canal. In some instances the body of thefilament may be configured to cut or tear through the trabecularmeshwork when the cannula is removed from the eye. In other instancesthe filament may be configured to disrupt trabeculocanalicular tissueupon advancement into or retraction from Schlemm's canal. In yet otherinstances the filament may be configured to be left within the canal tocontinuously deliver tension on the meshwork and maintain patency of thecanal.

In some variations the elongate member may comprise a lumen. Forexample, in one variation the elongate member may comprise amicrocatheter (e.g., a nylon microcatheter). In some of the instances inwhich the elongate member comprises a lumen, the elongate member may beconfigured to deliver a fluid composition. The fluid composition maytravel through a lumen of the elongate member and may be deliveredthrough an opening of the lumen. For example, as shown in FIG. 12, theelongate member (1200) may be a flexible tube having a lumen in fluidcommunication with an opening at the distal tip (1202). In somevariations, the distal end of the elongate member may be configured ormodified to aid delivery of the fluid composition into Schlemm's canal.For example, the distal end of the elongate member may comprise a cutout configured as a half tube. Additionally or alternatively to anopening at the distal tip, the elongate member may optionally comprise aplurality of openings through its wall that are spaced along the axiallength of the elongate member. In this variation, the fluid compositionmay be delivered from the reservoir through the openings in the elongatemember and into Schlemm's canal. This lateral ejection of fluid (e.g., aviscoelastic fluid) may in some instances enhance disruption of outflowtissues and enhance permeability to aqueous humor. It is understood thatthe openings can be of any suitable number, size and shape, and spacedalong the axial length of the elongate member (including the distal tip)in any suitable manner.

Drive Assembly

The delivery systems generally include a drive assembly. The driveassembly of the delivery system is generally configured to move anocular device, elongate member, and/or fluid composition into Schlemm'scanal. The drive assembly may also in some variations be configured toposition an ocular device within the canal, including advancing thedevice into the canal and retracting the device from the canal. Thedrive assembly may be at least partially contained within the housingand may include any suitable component or combination of componentscapable of providing the handle with universal functionality.

The drive assembly may convert an external input (e.g., motion of auser's thumb or finger) into motion of one or more components of thedelivery system. More specifically, the drive assembly may cause aslidable elongate member to be extended distally out of a cannula,and/or it may cause a slidable elongate member to be retractedproximally into a cannula. The drive assembly may also optionally causea fluid composition to be delivered from a reservoir through theelongate member and/or cannula.

Two or more of these effects (i.e., extension of the slidable elongatemember, retraction of the slidable elongate member, and/or delivery of afluid composition) may be actuated using the same actuation mechanism.This may allow for single-handed use of the delivery system. Forexample, if the actuation mechanism comprises a rotatable element (suchas one or more wheels, as in variations described herein), rotating therotatable element in a first direction may cause extension of theslidable elongate member, and rotating the rotatable element in a seconddirection may cause retraction of the slidable elongate member. If thedelivery system is configured to deliver a fluid composition, rotatingthe rotatable element (e.g., in the second direction) may also causedelivery of a fluid composition. The delivery of the fluid compositionmay be simultaneous with movement (e.g., retraction) of the slidableelongate member. In some of these instances, the fluid composition maybe delivered to the portion of Schlemm's canal in which the slidableelongate member is advanced; that is, the fluid composition may bedelivered to the same angle and length of Schlemm's canal as theextension of the elongate member. When the fluid composition issimultaneous with retraction of the elongate member, fluid compositionmay take the place of the slidable elongate member as it is retractedand may dilate Schlemm's canal and/or the collector channels at thatlocation in Schlemm's canal. Furthermore, the quantity of fluiddelivered may be tied to the amount of movement of the elongate member;that is, a certain predetermined, fixed volume of fluid composition maybe delivered via the elongate member (e.g., delivered out of the distalend of the elongate member) for a fixed amount of movement of theelongate member (e.g., a retraction distance) and for a fixed amount ofrotation of the rotatable element.

In some variations, the drive mechanism may be configured to allow thedelivery system to be used only once—that is, the drive mechanism mayprevent, for example, re-extension of the slidable elongate member aftera predetermined amount of extension and/or retraction. Exemplarymechanisms by which external input may be converted into motion of oneor more components of the delivery system are described in more detailbelow.

In some variations, the drive assembly includes components thattranslate rotational motion into linear motion. For example, the driveassembly may include a linear gear and a pair of pinion gear mechanisms.The linear gear may have teeth on its surface that engage correspondingteeth on the pinion gears. Each of the pinion gear mechanisms may alsobe coupled to a rotatable component (e.g., a wheel). Such coupling maybe accomplished with a pin that can be threaded through a centralopening in the rotatable component and pinion gear, and a nut thatsecures the rotatable component and pinion gear in a manner so thatrotation of the rotatable component also rotates the pinion gear andvice versa. The wheels may be attached to the pinion gear by one of thefollowing methods, for example: 1) the wheels and pinion gears aremolded as one part using plastic injection molding technology; 2) thewheels slide onto the pinion gear and are secured with adhesive; or 3)the wheels slide on the pinion gear and are mechanically fixed with afastener or a “press fit,” where the wheels are forced onto the piniongear and friction holds them secure. In all of the mentioned situations,the wheels and pinion gears may rotate coaxially, in the same direction,and at the same angular rate. In some variations, each of the piniongear mechanisms is coupled to at least two rotatable components. Inother variations, the drive assembly may be configured to include asingle rotatable component, a plurality of rotatable components, or norotatable component. The wheel may have markings or colorings toindicate degree of advancement or direction of advancement.

One variation of the drive assembly useful to include in the universalhandle comprises a linear gear, a pair of pinion gear mechanisms, andtwo rotatable components coupled to each pinion gear (for a total offour rotatable components). In other variations, the drive assemblyincludes a linear gear and a single pinion gear mechanism with twoassociated wheels. In variations with a pair of pinion gear mechanisms,the pinion gear mechanisms and associated wheels would be disposed oneither side of the linear gear. The pinion gears and linear gear wouldcontact each other, i.e., the teeth of the pinion gears would directlyengage corresponding teeth on the linear gear, and the wheels on oneside of the linear gear would contact the wheels on the opposite side ofthe linear gear. At least a portion of the wheels on each side of thelinear gear would extend outside of the housing. In this variation, thedrive assembly can be manipulated with one hand when in a firstconfiguration, and then manipulated with the same or the other hand whenflipped over to a second configuration. A drive assembly having suchflexible capability can be easily used by a surgeon who is right handdominant or left hand dominant, and may also be used in a procedure inwhich the handle is flipped during a procedure such that the cannula isfacing a first direction in a first portion of the procedure, and facinga second direction in a second portion of the procedure. In a furthervariation, the drive assembly may include one rotatable component on oneside of the handle and the “universal” feature of the handle provided bya cannula that itself can rotate instead of flipping the handle.

In the variation shown in FIG. 4A, delivery system (400) includes adrive assembly (402) having a linear gear (e.g., a rack) (404) and apair of pinion gear mechanisms (406). Both the linear gear and thepinion gear mechanisms have teeth that engage each other to translaterotational motion (of the pinion gear mechanisms (406)) to linear motion(of the linear gear (404)). Each of the pinion gear mechanisms (406) iscoupled to two rotatable components, shown in the figure as wheels(408), for a total of four rotatable components. The wheels (408) extendoutside of the housing (414) of the delivery system (400), and as such,may be rotated by one or more of the surgeon's fingers tocorrespondingly rotate the pinion gear mechanism (406) and thus advanceor retract the linear gear (404). The wheels (408) are coaxial with thepinion gear mechanism (406) and rotate in unison with the pinion gearmechanism. Movement of the linear gear (404) advances or retracts apositioning element (410) that is coaxially disposed and slidable withincannula (412). FIG. 4B shows the system of FIG. 4A in a second, flippedorientation. In the orientation of FIG. 4A, the cannula is oriented withthe curvature facing clockwise, while in the orientation of FIG. 4B, thecannula is oriented with the curvature facing counterclockwise. Theextension of wheels (408) outside of the housing (414) on either sidemay allow the delivery system (400) to be used in either orientation,with either hand, and on either of the patient's eyes. That is, theorientation of FIG. 4B can be used with the opposite hand or the samehand as the orientation of FIG. 4A, but when a different direction ofcannulation is desired (e.g., clockwise cannulation if counterclockwisecannulation was performed with the system in FIG. 4A).

Another variation of a drive assembly is shown in two differentperspective views in FIGS. 22A-22B. As depicted there, a drive assembly(2202) may comprise a linear gear (e.g., a rack) (2204) and a pair ofpinion gear mechanisms (2206). Both the linear gear and the pinion gearmechanisms have teeth that engage each other to translate rotationalmotion (of the pinion gear mechanisms) to linear motion (of the lineargear). More specifically, the linear gear (2204) may comprise teeth onboth a first side (2220) and a second side (2222), where the teeth onthe first side engage the first pinion gear mechanism, and the teeth onthe second side engage the second pinion gear mechanism. Each of thepinion gear mechanisms (2206) is coupled to two rotatable components,shown in the figure as wheels (2208), for a total of four rotatablecomponents. The wheels (2208) are coaxial with the pinion gearmechanisms (2206) and rotate in unison with the pinion gear mechanisms.The drive assembly may comprise one or more features to stabilize thepinion gear mechanisms or otherwise keep them in place. For example, thedrive assembly (2202) may comprise wheel spacers (2216) configured tosit between axles (2218) of the pinion gear mechanisms. Rotation of oneor more wheels (2208) may cause translation of the linear gear (2204).

As shown in FIGS. 22C and 23A-23B, the wheels (2208) may extend out ofthe housing (2334) of the delivery system, such that the wheels may berotated by a surgeon to correspondingly rotate the pinion gearmechanisms (2206) and thus advance or retract the linear gear (2204).The cannula (2344) may be slidable within the linear gear (2204), suchthat the cannula and wheels are fixed relative to each other andrelative to the housing (2334), while the linear gear (2204) translatesrelative to the housing. Because linear motion of the linear gear (2204)may be generated by rotational motion of either of the two pinion gearmechanisms (2206), which may in turn be generated by rotating any of thewheels (2208) extending from the housing (2334), the delivery system(2300) may be easily operated using a single hand with either the firstside or the second side facing upwards, and thus with the cannula (2344)facing a first direction or a second direction.

In other variations, one or both pinion gear mechanisms may be able tobe disengaged from the linear gear by biasing their position off axisfrom the linear gear. This action de-couples the pinion gear teeth tothe linear gear teeth to prevent linear gear movement. The pinion gearmechanism may also be able to be locked to prevent rotation by engagingan intersecting pin or feature that prevents wheel rotation.

Further variations of the drive assembly may not employ translation ofrotational motion to linear motion. For example, a slide (e.g., a fingerslide) on the handle that is fixed or detachably coupled to a gearwithin the housing of the handle (e.g., a linear gear as previouslydescribed). Here the drive assembly may be configured so thatadvancement or retraction of the slide causes advancement or retractionof an ocular device and/or elongate member, and/or delivery of a fluidcomposition into Schlemm's canal. In yet further variations, a buttonthat can be pressed or squeezed could be employed instead of a slide, ora foot pedal could be employed to deliver an ocular device, tool, and/orfluid composition.

Extending and Retracting the Elongate Member

In some variations, a proximal end of the elongate member may be fixedrelative to a portion of a drive assembly (e.g., the linear gear(2204)), while the distal end may be slidably and coaxially disposedwithin the cannula lumen. When the elongate member does not comprise alumen (e.g., is a filament), the elongate member may in some instancesbe attached to the drive assembly via crimping. When the elongate membercomprises a lumen, the elongate member may in some instances be bondedto the drive assembly (e.g., via an adhesive) in order to leave thelumen of the elongate member unobstructed. The cannula, in turn, may befixedly attached to the housing. In variations of the delivery systemsin which the handle is reusable and the cannula and elongate member aredisposable, a disposable assembly comprising the elongate memberpre-loaded within the cannula may be attached to the reusable handle viaany suitable mechanism, such as a threaded fastener or snap-in feature.

When the portion of the drive assembly is moved proximally or distallywithin the housing, this may cause corresponding movement of theelongate member relative to the cannula. That is, movement of theportion of the drive assembly toward the cannula (i.e., toward thedistal end of the housing) may cause the elongate member to move from aretracted position to an extended position, and movement of the portionof the drive assembly away from the cannula (e.g., toward the proximalend of the housing) may cause the elongate member to move from anextended position to a retracted position. An example of an elongatemember in an extended position is shown in FIGS. 22C-22D. As shown inthe view in FIG. 22D with the top portion of the housing (2334) removed,the linear gear (2204) is in a distal position. As such, the elongatemember (2346) is extended from cannula (2344).

Reservoir

The systems generally include a reservoir when a fluid composition is tobe delivered into Schlemm's canal. The reservoir may contain variousfluid compositions for delivery. Exemplary fluid compositions includesaline and viscoelastic fluids. The viscoelastic fluids may comprisehyaluronic acid, chondroitin sulfate, cellulose, derivatives or mixturesthereof, or solutions thereof. In one variation, the viscoelastic fluidcomprises sodium hyaluronate. In another variation, the viscoelasticcomposition may further include a drug. For example, the viscoelasticcomposition may include a drug suitable for treating glaucoma, reducingor lowering intraocular pressure, reducing inflammation, and/orpreventing infection, fibrosis, scarring, clotting, thrombosis,bleeding, or neovascularization. Drugs such as antimetabolites,vasoconstrictors, anti-VEGF agents, steroids, heparin,anti-inflammatories, nonsteroidal anti-inflammatories (NSAIDs), otheranticoagulants, fibrinolytic compounds, biologic agents, and genetherapy drugs may also be delivered in combination with the viscoelasticcomposition. Examples of glaucoma drugs include prostaglandins, betablockers, miotics, alpha adrenergic agonists, or carbonic anhydraseinhibitors. Anti-inflammatory drugs such as NSAIDs, corticosteroids orother steroids may be used. For example, steroids such as prednisolone,prednisone, cortisone, cortisol, triamcinolone, or shorter actingsteroids may be employed. Examples of antimetabolites include5-fluoruracil or mitomycin C. Examples of drugs or antibodies thatprevent neovascularization include bevacizumab, ranibizumab, and others.In still another variation, the system delivers the drug alone, withoutthe viscoelastic composition. Saline solution may also be the fluidemployed. In yet other variations, the system may be configured todeliver a gas, such as but not limited to air, an expansile gas (e.g.,SF6, C3F8).

In some variations, the reservoir may be at least partially defined by afluid assembly and the housing, and the linear gear within the handle.The fluid assembly may be made from any suitable material previouslymentioned for the cannula and the housing. The volume of fluid (inmicroliters) contained within the reservoir may range from about 2 μl toabout 1000 μl, or from about 2 μl to about 500 μl. In some variations,the reservoir volume may range from about 50 μl to about 100 μl.

The fluid composition may be preloaded in the reservoir or loaded intothe reservoir prior to use of the system, e.g., at the start of anocular procedure, so that the fluid can be delivered by a single deviceand by a single user. Again, this is in contrast to other systems thatuse forceps or other advancement tools to advance a fluid deliverycatheter into Schlemm's canal and/or devices containing viscoelasticfluid that are separate or independent from a delivery catheter orcatheter advancement tool, and which require connection to the deliverycatheter or catheter advancement tool during a procedure by, e.g., anassistant, or by the hand of the surgeon while the delivery catheter orcatheter advancement tool is held by another hand of the surgeon. Forexample, a loading component may be provided on the fluid assembly fortransfer of a fluid composition into the reservoir. The loadingcomponent may have any suitable configuration that provides reversiblesecurement of a fluid container, e.g., a syringe, cartridge, etc., tothe system, and loading of a fluid composition into the reservoir. Theloading component may be a luer fitting or include a one-way valve.

An exemplary delivery system comprising a reservoir is shown in FIGS.23A-23F. Shown there with (FIGS. 23A, 23B, and 23E), without (FIGS. 23Cand 23D), and partially without (FIG. 23F) a housing (2334), thedelivery system (2300) comprises a fluid assembly (2316) comprising areservoir (2302). In an exemplary method, a fluid composition may beloaded into the reservoir (2302) through a proximal opening (2328) via aproximal seal (2318). As best shown in FIG. 23E, the distal end of thereservoir (2302) may be formed by a plunger (2338) (explained in moredetail below) and a distal seal (2354).

The proximal seal (2318) may be a mechanical seal located at theproximal end of the reservoir (2302) and comprising a ball bearing(2324) spring-biased against an o-ring or gasket (2330) to seal closedthe reservoir. A loading tool (2326) (e.g., a nozzle) may be used toopen the seal by pressing against the ball bearing (2324) to move itproximally toward an open position. While the proximal seal (2318) isopen, the fluid composition may be loaded into the reservoir. Afterloading of the fluid composition, the loading tool (2326) may beremoved, allowing the ball bearing (2324) to return to its closedposition. The close-up cross-sectional view in FIG. 23E shows theproximal opening (2328) and ball bearing (2324). An o-ring or gasket(2330) sits between the ball bearing (2324) and a spring (2332), suchthat force from the spring presses the ball bearing into the gasket toform a seal between the ball bearing and gasket in the closed position.The loading tool (2326) is configured to fit into the proximal opening(2328) to press against the ball bearing (2324). The distally orientedforce against the ball bearing (2324) moves it distally into the openposition, compressing the spring (2332), and creating an opening betweenthe ball bearing and the gasket (2330), through which the fluidcomposition may flow. When the loading tool (2326) is removed from theproximal opening (2328), the spring (2332) pushes the ball bearing(2324) proximally back into the closed position.

It should be appreciated that in other variations, the reservoir maycomprise other types of seals allowing a fluid composition to be loadedinto the reservoir. For example, FIG. 24 depicts an alternativevariation of a delivery system (2400), wherein the seal comprises amembrane (e.g., a silicone membrane). As shown, a fluid composition maybe loaded (after movement of the optional lock (2404)) into thereservoir by puncturing the membrane with a needle (2402) (e.g., a 25gauge needle). In yet other variations, the delivery systems describedherein may be configured to receive a prefilled cartridge comprising afluid composition. For example, the handle and fluid assembly may beconfigured such that a prefilled cartridge can be inserted into thefluid assembly.

In order to load the reservoir, it may be desirable to at leasttemporarily secure the fluid assembly in place in order to allowapplication of distal force to the seal. In some variations, thedelivery system may comprise a lock configured to hold the fluidassembly in place while a fluid composition is injected into thereservoir. However, it should be appreciated that in other variationsthe delivery system may not comprise a lock. In variations having alock, it may be desirable for the lock to be removable from the deliverysystem (or to otherwise release the fluid assembly) in order to allowthe fluid assembly to translate relative to the housing after thereservoir is loaded. Translation of the fluid assembly may allow forextension of the slidable elongate member and/or injection of the fluidcomposition during the procedure, as is described in more detail herein.

In variations of the delivery systems having a lock, the lock mayoptionally additionally act as a cap to protect a distal opening to thereservoir. In these variations, the lock may comprise a firstconfiguration in which it both holds the reservoir in place and coversthe proximal opening to the reservoir, and a second configuration inwhich it holds the reservoir in place but allows the proximal opening tothe reservoir to be accessed, such that the reservoir can be loaded witha fluid composition. In some instances, the lock may rotate from thefirst position to the second position.

FIGS. 25A-25D illustrate an exemplary lock (2502). As shown there, thelock (2502) may comprise a pin (2508) configured to fit into an opening(2504) in the handle (2506) of the delivery system (2500). In a firstconfiguration, shown in FIG. 25B, the lock (2502) may be inserted intothe opening (2504) in the handle and may cover the proximal opening(2510). The lock (2502) may comprise a protrusion (2518) configured tointerface with the proximal opening (2510) to stabilize the lock in thefirst configuration. In a second configuration, shown in FIGS. 25C-25D,the lock (2502) may remain inserted into the opening (2504) but maypivot within the opening to expose the proximal opening (2510) to allowloading of the reservoir (2512). When the pin (2508) is inserted intothe opening (2504), the pin may restrict movement of the reservoir(2512) relative to the housing. This may allow a loading tool (2514) toapply force through the proximal opening (2510) to open the proximalseal (2516) of the reservoir (2512), without the reservoir slidingdistally within the handle (2506). Restricting movement of the reservoir(2512) relative to the handle (2506) may prevent motion of the reservoiror other internal components of the delivery system before use (e.g.,during transit). Once loading of the reservoir (2512) is complete, thelock (2502) may be removed from the opening (2504), as shown in FIG.25A, at which point the reservoir (2512) may no longer be restricted bythe lock from moving relative to the housing.

Delivering a Fluid Composition

The delivery systems described herein may be configured to deliver fluidto Schlemm's canal. The fluid may be delivered in a volume that providessufficient force to disrupt Schlemm's canal and surroundingtrabeculocanalicular tissues. Exemplary disruptive volumes may be about1 μl, about 2 μl, about 3 μl, about 4 μl, about 5 μl, about 6 μl, about7 μl, about 8 μl, about 9 about 10 μl, about 11 μl, about 12 μl, about13 μl, about 14 μl, about 15 μl, about 16 μl, about 17 μl, about 18 μl,about 19 or about 20 μl. In some variations, the disruptive volume fluidmay range from about 1 μl to about 50 or from about 20 μl to about 50μl.

As mentioned above, a elongate member may be coaxially disposed withinthe cannula lumen. In variations of the delivery system configured todeliver a fluid composition, the elongate member may comprise a lumen.The lumen of the elongate member may be operatively connected to areservoir for delivery of a fluid composition into Schlemm's canal. Theelongate member generally has a proximal end, a distal end, and a wallthat defines the lumen extending therethrough. However, in someinstances, the delivery system lacks an elongate member conduit, and thefluid composition is delivered solely through the cannula. In otherinstances, two elongate members may be employed that each simultaneouslyadvance through the canal in both clockwise and counterclockwisedirections to more rapidly cannulate Schlemm's canal and delivertherapy.

When the delivery systems are employed to deliver a fluid composition,the fluid composition may be preloaded in a reservoir of the system orloaded into the reservoir prior to use of the system. An exemplarydelivery system for delivering a fluid composition into Schlemm's canalis shown in FIGS. 10A and 10B. Referring to FIG. 10A, delivery system(1000) includes a universal handle (1002) having a grip portion (1004)and a housing (1006). Housing (1006) has a proximal end (1008) and adistal end (1010). A cannula (1012) is coupled to and extends from thehousing distal end (1010). A drive assembly (1014) is substantiallycontained within the housing (1006) that actuates movement of a slidableelongate member (not shown). The cannula (1012) and drive assembly(1014) have the same configuration as that shown and described in FIGS.3 and 4A-4B for the system tailored for ocular device implantation, andthus are not described in detail here.

The delivery system (1000) also includes a fluid assembly (1016) (shownin FIG. 10B) within the handle (1002) having a loading component (1018)that is configured to allow transfer of a fluid composition from anexternal source into a reservoir defined by the fluid assembly andlinear gear (1020). A slidable elongate member (1022) is coaxiallydisposed within the cannula lumen that is in fluid communication withthe reservoir. As previously stated, in a tool-based system that doesnot deliver an implant or a fluid, the system may not include areservoir.

In an exemplary method, as illustrated by FIGS. 11A-11C, a fluidcomposition may be transferred into a reservoir (1102) of system (1100)via loading through loading component (1104). As shown in the figures,reservoir (1102) is defined by the fluid assembly (1106) and the lineargear (1108). Linear gear (1108) has a proximal end (1110) and a distalend (1112), and a lumen (1114) extending from the proximal end (1110) tothe distal end (1112). Lumen (1114) is in fluid communication with thelumen (not shown) of the slidable elongate member (1118). To deploy thefluid composition out of the reservoir (1102), linear gear (1108) isretracted in the direction of the arrow (FIG. 11B) so that reservoir(1102) becomes pressurized. Retraction can be accomplished by rotationof pinion gear mechanisms (1120). Once a sufficient amount of pressurehas been created in the reservoir (1102) the fluid composition containedtherein is injected through linear gear lumen (1114) and the lumen ofelongate member (1118) into Schlemm's canal.

Here, any fluid that is delivered flows through the distal end (1202) toreach Schlemm's canal. In other variations, the slidable elongate member(1300) may be configured to include a plurality of openings spaced alongits axial length. The openings may have any suitable shape, e.g., slots(1302) (FIG. 13A) or circles (1304) (FIG. 13B). Fluid compositionsdelivered using the elongate members depicted in FIG. 13A and FIG. 13Bmay partially flow out of the elongate member through the openings andpartially out through the distal end of the elongate member. The distalend of the elongate member may also be configured as a half tube (1306)(FIG. 13C).

Some variations of the fluid assembly include a locking mechanism forpreventing movement of the assembly within the handle, e.g., when thelinear gear is being advanced or retracted. The locking mechanism maycomprise a ratchet pawl, a combination of ratchet pawls or any othersuitable mechanism that can be locked to prevent movement of the fluidassembly, and unlocked to allow movement of the fluid assembly.

Referring back to FIGS. 23A-23F, another exemplary delivery system(2300) for delivering a fluid composition into Schlemm's canal shownthere may comprise a housing (2334) and a cannula (2344) extending fromthe distal end of the housing. A drive assembly (2202) (described abovewith respect to FIGS. 22A-22D) may be located within the housing (2334),as may be a fluid assembly (2316) (described in more detail above). Asdescribed above, the drive assembly (2202) may comprise a linear gear(2204) and a pair of pinion gear mechanisms (2206) coupled to wheels(2208). The delivery system (2300) may comprise a slidable elongatemember (2336). A proximal end of the elongate member may be fixedrelative to the linear gear (2204), while the distal end of the elongatemember may be slidably and coaxially disposed within the lumen of thecannula (2334). A reservoir (2302) of the fluid assembly (2316) may befluidly connected to a lumen of the elongate member. For example, aplunger (2338) comprising a lumen may fluidly connect the reservoir(2302) to the lumen of the elongate member. The proximal end (2350) ofthe plunger (2338) may be located slidably within the reservoir (2302),and the distal end (2352) of the plunger may be fixedly attached to thelinear gear (2204) of the drive assembly (2202).

The fluid assembly (2316) and the drive assembly (2202) may be connectedvia a linkage (2348), as best shown in FIG. 23D. (The delivery system(2300) is shown without the linkage assembly in FIG. 23A in order tobetter show other components.) The linkage (2348) may be configured toallow the fluid assembly (2316) and drive assembly (2202) to be moved asa unit, and may allow limited movement of the fluid assembly and driveassembly relative to each other. In some variations, the linkage (2348)may allow the fluid assembly (2316) to be moved closer but not fartherfrom the drive assembly (2202). For example, as best shown in FIG. 23D,the proximal end (2340) of the linkage (2348) may be fixedly attached tothe fluid assembly (2316). The distal end (2342) of the linkage (2348)may be attached via a one-way ratchet to the linear gear (2204) of thedrive assembly (2202). The distal end (2342) may be able to be moveddistally along a track in the linear gear (2204), but teeth in the trackmay resist proximal movement of the distal end (2342) along the track.As such, the fluid assembly (2316) may be able to be moved distallytoward the linear gear (2204), such that the fluid assembly and lineargear are brought closer together (via shortening of the portion of thelinkage (2348) between the fluid assembly and the linear gear), but thefluid assembly may not be able to be moved proximally away from thelinear gear. It should be appreciated that in other variations, alinkage may be fixedly attached to the linear gear and slidably attachedto the fluid assembly.

Thus, the linear gear (2204) and the fluid assembly (2316) may bemovable relative to each other and may be movable within the housing(2334). Movement of the linear gear (2204) and fluid assembly (2316)relative to each other, as well as relative to the housing (2334), maycause one or more effects, including extension and retraction of theslidable elongate member and/or delivery of a fluid composition. Morespecifically, because the proximal end (2350) of the plunger (2338) maybe located slidably within the reservoir (2302) and the distal end(2352) of the plunger may be fixedly attached to the linear gear (2204),movement of the reservoir closer to linear gear may cause proximalmovement of the plunger within the reservoir. This may cause the lengthof the plunger (2338) located within the reservoir (2302) to increase.The portion of the plunger (2338) within the reservoir (2302) maydisplace fluid within the reservoir. The displaced fluid may movedistally through the lumen of the plunger (2338), through the lumen ofthe elongate member (2336), and may be delivered out through a distalopening of the lumen of the elongate member.

Additionally, as mentioned above, movement of the linear gear (2204)relative to the housing (2334) may cause the slidable elongate member(2336) to extend or retract. The linear gear (2204) may be moveablebetween proximal and distal positions via rotation of the wheels (2208),while the wheels (2208) remain fixed relative to the housing (2334).Because the proximal end of the elongate member may be fixed relative tothe linear gear (2204) and the distal end of the elongate member may beslidable within the lumen of the cannula (2344), when the drive assembly(2202) is in a proximal position, the elongate member maycorrespondingly be in a retracted position relative to the cannula(2344). When the elongate member is in the retracted position, thedistal end of the elongate member may be located within the cannula(2344) (e.g., proximal to the distal tip of the cannula). When the driveassembly (2202) is in a distal position, the elongate member maycorrespondingly be in an extended position relative to the cannula(2344). When the elongate member (2336) is in the extended position, thedistal end of the elongate member may extend out of the cannula (e.g.,distal to the distal tip of the cannula).

Relative motion of the drive assembly (2202), fluid assembly (2316), andhousing (2334) may thus be used to extend the slidable elongate member(2336) within Schlemm's canal, and to retract the elongate member withinSchlemm's canal while simultaneously delivering fluid. The deliverysystem (2300) may start in a configuration where the fluid assembly(2316) and linear gear (2204) are separated by the full distance of thelinkage (2348), the fluid assembly is located at the proximal end of thehousing (2334), and the slidable elongate member is in a retractedposition within the cannula (2344). This configuration is shown in FIGS.23A-23D. The wheels (2208) may be rotated in a first direction toadvance the linear gear (2204) distally within the housing (2334). Thelinkage (2348) may cause the fluid assembly (2316) to move an equaldistance distally within the housing, maintaining the spacing betweenthe fluid assembly and linear gear (2204). As the linear gear (2204)advances, the elongate member (2336) may move from the retractedposition to an extended position. This may cause the elongate member(2336) to travel though Schlemm's canal. This configuration is shown inFIG. 23F, which depicts the delivery system (2300) without a top portionof the housing (2334) to show the linear gear (2204) in a distalposition. As can be seen there, the elongate member (2336) is in anextended position relative to the cannula (2344), and the fluid assembly(2316) is also in a distal position within the housing (2334).

The wheels (2208) may then be rotated in a second direction to retractthe linear gear (2204) proximally within the housing (2334). This maycause the slidable elongate member (2336) to move from the extendedposition to the retracted position. However, the fluid assembly (2316)may not correspondingly move proximally within the housing (2334). Thehousing (2334) may comprise interior teeth (2446) near the fluidassembly (2316) configured to engage exterior teeth on the fluidassembly. These teeth may allow the fluid assembly (2316) to movedistally within the housing (2334) but not proximally within thehousing. As such, when the linear gear (2204) is retracted within thehousing (2334), the fluid assembly (2316) may remain fixed relative tothe housing. The linear gear (2204) and fluid assembly (2316) maytherefore move closer together, with the linkage (2348) moving distallyalong a track in the linear gear (2204) to accommodate this movement. Asthe linear gear (2204) and fluid assembly (2316) move closer together,the plunger (2338) may displace fluid within the reservoir (2302), asdescribed in more detail above. The fluid may then travel through alumen of the plunger (2338) and be delivered through the lumen of theelongate member (2336).

In this way, as the elongate member is retracted, fluid may be deliveredsimultaneously out of the elongate member. The fluid may take the placeof the elongate member as it is retracted, and as such, the fluid may bedelivered to an angle and length of Schlemm's canal that is the same asthe angle and length about which the elongate member was advanced. Afixed, predetermined volume of fluid may be delivered for a given amountof retraction of the elongate member, due to displacement of the fluidin the reservoir by the plunger, and both the retraction of the elongatemember and the delivery of a fluid composition may be effectuated by asingle user motion (rotation of a wheel (2208)). In some instances, fullretraction of the elongate member may result in the delivery of betweenabout 2 μl and about 9 μl of fluid. In some of these instances, fullretraction of the elongate member may result in the delivery of about4.5 μl of fluid. As the elongate member (2336) is retracted, thedelivery system (2300) may produce audible and/or tactile clicks atincrements. These clicks may, for example, be due to the ratcheting ofthe distal end (2342) of the linkage (2348) distally relative to thelinear gear (2204). Each click may correspond to a fixed, predeterminedvolume of fluid, in some cases, about 0.5 μl.

In some variations, the delivery systems may be configured to allow fora fixed cumulative amount of extension and/or retraction of the slidableelongate member. The fixed cumulative amount of extension/retraction maycorrespond, for example, to the full circumference of Schlemm's canal,two full circumferences of Schlemm's canal, or any desired distance.Exemplary fixed cumulative amounts may be, but are not limited to, about39 mm to about 41 mm, about 38 mm to about 40 mm, about 35 mm to about45 mm, about 78 mm to about 82 mm, about 76 mm to about 80 mm, or about70 mm to about 90 mm. The delivery systems may additionally oralternatively be configured to allow for a fixed cumulative delivery offluid (e.g., in some variations about 9 μl of fluid). For example, indelivery system (2300), as described above the fluid assembly (2316) maybe able to move distally within the housing (2334) but not proximallywithin the housing, and the fluid assembly may be able to be movedtoward but not away from the linear gear (2204). As such, with eachextension of the slidable elongate member, the linear gear (2204) andthe fluid assembly (2316) may move distally; but with each retraction ofthe elongate member, the linear gear may move proximally while the fluidassembly remains fixed. The delivery system (2300) may comprise a stop(e.g., a protrusion on the interior wall of the housing) that mayprevent the fluid assembly (2316) from moving distally beyond a certainpoint. Once the fluid assembly (2316) has reached its distal-mostposition, neither the fluid assembly nor the linear gear (2204) may bemoved distally or proximally, and the wheels (2208) may no longerrotate. The distance between the initial position of the fluid assembly(2316) and its final distal-most position may dictate the fixedcumulative amount of extension/retraction of the slidable elongatemember and the fixed cumulative delivery of fluid. It should beappreciated, however, that other variations of the delivery systems maynot have a limited cumulative amount of extension and/or retraction ofthe elongate member; that is, some delivery systems may be able to berepeatedly extended and retracted without a fixed limit.

It should be appreciated that the delivery system (2300) may allow theslidable elongate member to be advanced and retracted multiple times, solong as the total, cumulative amount is below the limit. Indeed, in somevariations, the maximum amount that the elongate member may be advancedwithout retraction may be less than that total, cumulative amount. Forexample, the elongate member may be advanced a first time approximatelyhalfway around Schlemm's canal (i.e., 180 degrees, or approximately 19mm to about 20 mm) in a first direction, which may be the maximum amountthat the elongate member may be advanced without retraction. Theelongate member may then be fully retracted (during which fluid may bedelivered). After this first extension, the fluid assembly (2316) mayhave moved half of its maximum distance, and its distance to the lineargear (2204) may have decreased by approximately half of its totalpossible decrease. The delivery system (2300) may then be rotated aboutthe handle, and the elongate member may be advanced a second timeapproximately halfway around Schlemm's canal in a second direction. Theelongate member may then be retracted (during which fluid may bedelivered). At the conclusion of the second extension, the fluidassembly (2316) may be located as its distal-most position, and itsdistance to the linear gear (2204) may be at its minimum. At this point,the elongate member may no longer be advanced, no further fluid may bedeliverable, and the wheels may no longer rotate.

Devices not Configured to Deliver a Fluid

It should be appreciated that not all delivery systems described hereinmay be configured to deliver a fluid composition. Devices not configuredto deliver a fluid composition may operate similarly to delivery systemsconfigured to deliver a fluid composition, but retraction or advancementof the elongate member may not cause simultaneous delivery of a fluidcomposition. In some instances, the delivery systems may be identical tothose configured to deliver a fluid composition, but may not be loadedwith fluid composition. In other instances, the elongate member ofdelivery systems not configured to deliver a fluid composition need notcomprise a lumen. Similarly, delivery systems not configured to delivera fluid composition need not comprise a reservoir or plunger. In placeof the reservoir, the delivery system may comprise a solid placeholdercomponent having a similar exterior shape to the fluid assembly. Theplaceholder component may be connected to the linear gear of thedelivery system via a linkage, which may or may not be integral to theplaceholder component. This may allow many of the components betweendelivery systems configured to deliver a fluid composition and notconfigured to deliver a fluid composition to be interchangeable, whichmay simplify manufacturing. Thus, like delivery systems configured todeliver a fluid, systems not configured to deliver a fluid may or maynot be configured to allow for a fixed cumulative amount of extensionand/or retraction, as described in more detail herein.

Some delivery systems not configured to deliver a fluid composition maybe configured such that the elongate member disrupts the trabecularmeshwork. In some variations, the elongate member may be configured suchthat advancement and/or retraction of the elongate member may disruptthe trabecular meshwork, and the elongate member may comprise one ormore features to promote disruption of the trabecular meshwork uponadvancement or retraction, such as disruptive components on the distalend of the elongate member, such as barbs, hooks, balloons, or the like.In other variations, the elongate member may be configured such that thebody of the elongate member is configured to cut or tear the trabecularmeshwork. For example, the delivery system may be configured such thatthe elongate member may be advanced out of the cannula and aroundSchlemm's canal; if the cannula is then removed from the eye withoutretracting the elongate member, the body of the elongate member may cutor tear the trabecular meshwork as the cannula is removed. The body ofthe elongate member may be configured to “unzip” the meshwork, cuttingor tearing from a first location of the trabecular meshwork close to thecannula tip (i.e., at the proximal end of the elongate member) andcontinuing around the trabecular meshwork toward the distal end of theelongate member. The elongate member may be configured to apply adisruptive force to cut or tear the meshwork at one location of themeshwork at a time, sequentially around Schlemm's canal, rather than adisruptive force that simultaneously cuts or tears the meshworkthroughout all of the trabecular meshwork being cut or torn.

Implanting an Ocular Device

The cannula of the systems described herein may also deliver varioussurgical tools by ab-interno methods. For example, catheters, wires,probes, and other tools may also be employed ab-interno to accessSchlemm's canal and then to create holes, partial thickness disruptions,or perforations in discreet locations or all along the trabecularmeshwork or inner wall of Schlemm's canal. The surgeon may also advancethe tools all the way across the canal and through the collector channelouter wall to access the sclera and subconjunctival space (again allfrom an ab-interno approach) to make incisions that create a sclerallake into which aqueous can drain to the scleral veins orsubconjunctival space or to deliver an ocular device ab-interno thatresides and drains into the scleral lake or sub conjunctival space fromthe anterior chamber or Schlemm's canal.

When the delivery system is used to implant an ocular device, thecannula may have a slidable positioning element coaxially disposedwithin the cannula lumen. The slidable positioning elements generallyinclude an engagement mechanism for manipulating, e.g., releasablyengaging, advancing and/or retracting, an ocular device. Exemplaryengagement mechanisms are depicted in FIGS. 5-9.

In FIG. 5A, the engagement mechanism (500) comprises a first jaw (502)and a second jaw (504). In their closed configuration (as shown in FIG.5A), the jaws (502, 504) are constrained within cannula (512) and holdan ocular device (506) comprising a support (508) and at least onefenestration (510). When the jaws (502, 504) are advanced out of cannula(512) they are no longer constrained, and thus take the form of theiropen configuration, as shown in FIG. 5B. Opening of the jaws (502, 504)releases ocular device (506) from the engagement mechanism (500). Atleast one tine (514) may be provided in the first jaw (502) and at leastone aperture (516) may be provided in the second jaw (504) to helpsecure a fenestrated ocular device when the jaws are in their closedconfiguration. In FIG. 6, a variation of an engagement mechanism (600)is shown where a first jaw (602) and a second jaw (604) include both atine (606) and an aperture (608) to help grasp a fenestrated oculardevice (610).

Referring to FIGS. 7A-7B, further exemplary engagement mechanisms aredepicted. In FIG. 7A, engagement mechanism (700) comprises complementarymating elements. Specifically, engagement mechanism (700) includes afemale element, notch (702) that is configured to interface with acomplimentary male element (704), shown as a hook-like projection on theocular device (706). Here the notch (702) may be fabricated at the endof a hypodermic tube (708) (which would serve as the positioningelement). Instead of notch (702), the female element of the engagementmechanism (710) may include an opening (712), as shown FIG. 7B, whichinterfaces with male element (704) on the ocular device (706). In FIG.7B, the positioning element (714) may be fabricated from a metal wire orrod and the opening (712) created via laser machining or other processesknown in the art.

In other variations, the engagement mechanism may be configured as shownin FIGS. 8A and 8B. In those figures, engagement mechanism (800)comprises a looped portion (802). It may be beneficial to use thisparticular engagement mechanism with an ocular device (804) including aclasp (806) with arms or tabs (808) having a closed configuration and anexpanded configuration. Similar to the variation shown in FIGS. 5A and5B, tabs (808) are constrained in their closed configuration within thecannula (810) prior to advancement out of the cannula (810). In theirconstrained configuration, tabs (808) engage the looped portion (802) ofthe engagement mechanism (800) to prevent release of the ocular device(804) from the system. When the looped portion (802) of the engagementmechanism (800) is advanced sufficiently so that tabs (808) are nolonger constrained by cannula (810), tabs (808) take on their expandedconfiguration to thus release the ocular device (804) from the loopedportion (802) and into Schlemm's canal, as shown in FIG. 8B.

Another exemplary engagement mechanism (900) is shown in FIG. 9comprising a coiled portion (902) and a hook (904). When an oculardevice (906) having at least one fenestration (908) (e.g., a proximalfenestration) is to be implanted, the hook (904) may be releasablyengaged to the fenestration (908). The ocular device (906) may bedisengaged from the hook by the application of gentle force on the coil(902) or by another component (not shown) that can be advanced over thecoil (902) to push the device (906) off the hook (904). It may beadvantageous to use the hook (904) when retraction of the ocular device(906) is desired.

The ocular delivery systems may further include a slidable positioningelement coaxially disposed within the lumen of the cannula forcontrolled implantation of an ocular device within Schlemm's canal. Thepositioning element generally comprises a proximal end, a distal end,and an engagement mechanism at the distal end. The ocular device isgenerally releasably coupled to the engagement mechanism. Thepositioning element may be advanced to deploy an ocular device withinthe cannula into Schlemm's canal, or it may be retracted to help withpositioning and/or repositioning of an ocular device, or disengagementof an ocular device from the engagement mechanism.

Some variations of the engagement mechanism include a proximal coiledportion and a distal hook. When an implant having at least onefenestration (e.g., a proximal fenestration) is to be implanted, thehook may be releasably engaged to the fenestration. The ocular devicemay be disengaged from the hook by the application of gentle force onthe coil or by another component that can be advanced over the coil topush the device off the hook or by using shape memory materials thatpassively disengages when exiting the cannula. It may be advantageous touse the hook when retraction of the ocular device is desired. Thesurgeon may simply move the delivery system and engagement mechanism sothat it disengages any fenestration or notch on the implant.

In another variation, the engagement mechanism includes opposing jaws.Here the engagement mechanism may include a first jaw and a second jaw,where the jaws have a closed configuration and an open configuration.The jaws may be used to grip and manipulate the ocular device, andreleasably couple the ocular device to the positioning element. The jawsmay be formed by splitting or bifurcating the distal end of a wire,e.g., by laser cutting. The grasping force of the jaws may be achievedby constraining the jaws within the cannula. The ocular device may bereleased once the jaws are advanced out of the cannula and expand. Thejaws may also be pivotably connected. In yet another variation, thefirst jaw may include at least one tine, and the second jaw may includeat least one aperture for receiving the tine when the jaws are in theclosed configuration.

In further variations, the engagement mechanism comprises a loopedportion. This variation of the engagement mechanism will typically beused with an ocular device comprising a spring-like clasp at itsproximal end, where the clasp has a collapsed configuration and anexpanded configuration. The clasp is generally fabricated in theexpanded position. Thus, when a device having a clasp is disposed withinthe cannula, the first and second arms or tabs of the clasp may collapsearound the looped portion of the engagement mechanism. Once the claspedportion of the device has exited the cannula, the arms or tabs mayexpand to release the ocular device from the looped portion.

Still another variation of the engagement mechanism includes a female tomale interface. For example, the engagement mechanism may comprise anotch configured to interface with a complimentary mating element (e.g.,a tab) on the ocular device. The notch (female component) may be formedwithin hypodermic tubing or may be made by creating a fenestrationthrough the distal end of a positioning element made from a solid wireor element, and the tab or hook (male component) may formed as part ofthe ocular device and may be inserted into the fenestration or notch inthe positioning element. With this configuration, the ocular device maybe released from the positioning element as it is advanced out of thecannula either by the surgeon's manipulation or by shape setting of thepositioning element that causes it to passively detach from the oculardevice or both.

II. Kits

The delivery systems described herein may be placed in specializedpackaging. The packaging may be designed to protect the systems, and inparticular, to protect the cannula. It may be desirable for thepackaging to prevent contact between the distal tip of the cannula andany other object or surface. In order to do so, the packaging maycomprise one or more elements configured to secure a delivery system tothe packaging at one or more locations proximal to the distal tip of thecannula. Securing the delivery system at at least two locations proximalto the distal tip of the cannula may be desirable to limit the abilityof the delivery system to pivot relative to the packaging.

In one exemplary variation, the packaging may comprise a tray comprisinga recess having a shape generally corresponding to the shape of thedelivery system and comprising one or more pinch points configured tosecure the delivery system at locations proximal to the cannula. FIG.26A shows an exemplary tray (2604) for a delivery system (2600). Tray(2604) may comprise a recess (2606) configured to receive the deliverysystem (2600). The tray (2604) may comprise first (2608) and second(2610) distal pinch points and first (2612) and second (2614) proximalpinch points configured to secure the delivery system (2600) within therecess (2606). When the delivery system (2600) is secured within thetray (2604), the cannula (2602) of the delivery system may be suspendedsuch that the cannula is not in contact with the tray, and the pinchpoints may limit pivoting of the delivery system (2600) in a way thatcould cause the cannula (2602) to come into contact with the tray. Thepinch points may be configured to safely secure the delivery system(2600) within the tray (2604), while also allowing a user to remove thedelivery system from the tray in a controlled fashion. In variations inwhich the kits described here comprise additional components, thepackaging may be designed to hold these additional components. Forexample, FIG. 26B shows an exemplary tray (2626) comprising a recess(2628) configured to hold a loading tool (2624) and a delivery system(2620). As shown in FIG. 26C, a tray (2640) may be configured to besealed with a lid (2642) (e.g., heat sealed) and placed within a box(2644). The box (2644) may optionally further contain instructions foruse (2646). The lid (2642) and/or box (2644) may optionally have labels(2648) affixed thereto.

It should be appreciated that the packaging may have otherconfigurations that protect the distal tip of the cannula. For example,in another variation, the packaging may comprise a stiff planar sheet towhich the delivery system may be attached in an orientation such thatthe cannula is not in contact with the planar sheet. The delivery systemmay be attached (e.g., via ties or other materials wrapped around thehousing) at two or more points along the housing in order to preventmovement of the delivery system relative to the planar sheet. It may bedesirable to protect the cannula on at least two sides; for example, aportion of the planar sheet near the cannula may be bent around thecannula to protect the cannula on at least two sides, or a second stiffplanar sheet may be attached to the delivery system opposite the firstplanar sheet.

Some kits described herein may comprise multiple delivery systems. Forexample, a kit may comprise two delivery systems. In some variations,the kit may comprise two of the same system, such that, for example, thefirst delivery system may be used in a first eye of the patient and thesecond delivery system may be used in the second eye of the patient. Inother variations, the kit may comprise two different systems. Forinstance, the first delivery system may be configured to deliver a fluidcomposition, and the second delivery system may not be configured todeliver a fluid composition, but may instead be configured to disruptthe trabecular meshwork using the elongate member. Kits comprisingmultiple systems may be packaged in any suitable way. For example, FIG.27A shows a kit comprising two delivery systems (2700, 2702) in astacked configuration (shown without outer packaging), and FIG. 27Bshows a kit comprising two delivery systems (2704, 2706) in aside-by-side configuration (shown without outer packaging). Again,delivery systems (2700, 2702) may both be configured to deliver a fluidcomposition, may both be configured not to deliver a fluid composition(e.g., may be configured to deliver an elongate member to disrupt thetrabecular meshwork), or one may be configured to deliver a fluidcomposition and the other may not. Similarly, delivery systems (2704,2706) may both be configured to deliver a fluid composition, may both beconfigured not to deliver a fluid composition, or one may be configuredto deliver a fluid composition and the other may not.

Some kits may comprise ocular implants in addition to one or moredelivery systems as described herein. For example, a kit may compriseone or more devices configured to be implanted into Schlemm's canal,which may be generally configured to maintain the patency of Schlemm'scanal without substantially interfering with transmural fluid flowacross the canal. The kits may comprise one or more ocular implants suchas, but not limited to, stents for placement in Schlemm's canal. In somevariations, the ocular implants may be one or more of those disclosed inU.S. Pat. No. 7,909,789, which was previously incorporated by referencein its entirety, and U.S. Pat. No. 8,529,622, which was previouslyincorporated by reference in its entirety. In one variation, the devicemay comprise a twisted ribbon member comprising a double helixcomprising a first elongated edge and a second elongated edge and aplurality of struts extending between the elongated edges in a directionsubstantially normal to a central longitudinal axis of the twistedribbon member. The struts may define a plurality of fenestrations spacedalong at least a portion of the length of the twisted ribbon member.

III. Methods

Methods for treating conditions of the eye and/or methods for implantingan ocular device, delivering a fluid composition into Schlemm's canal,and/or delivering a tool into Schlemm's canal using the systemsdescribed above are also provided. In some instances, treatingconditions of the eye may result in increased aqueous humor drainage,reduced resistance to aqueous outflow, and/or reduced intraocularpressure. Some methods described herein may dilate Schlemm's canal,dilate the collector channels, and/or break any septae that may obstructcircumferential flow through Schlemm's canal. Dilation of Schlemm'scanal may disrupt obstructed inner walls of the canal, stretch thetrabecular meshwork, and/or increase the trabecular meshwork's porosity.This may improve the natural aqueous outflow pathway. The dilation maybe performed by advancement of a tool (e.g., a slidable elongate memberas described herein). Additionally or alternatively, the dilation may beperformed by delivery of a fluid composition (e.g., a viscoelastic fluidas described herein). Additionally or alternatively, some methodsdescribed here may comprise performing a trabeculotomy to cut trabecularmeshwork. Additionally or alternatively, some methods described here maycomprise implanting an ocular device within Schlemm's canal. In someinstances, the systems described herein may be used in performingab-interno trabeculotomy, ab-interno transluminal trabeculotomy, clearcorneal trabeculotomy, clear corneal transluminal trabeculotomy,ab-interno canaloplasty, and/or clear corneal canaloplasty. The deliverysystems may also in some instances be used for lysing of anteriorchamber synechiae, viscogonioplasty, assisting with intraocular lensexchange, levitating a dropped lens or foreign body, and/orrepositioning of prolapsed iris tissue.

The methods are generally single-handed, single-operator controlledmethods that are minimally invasive, e.g., they are tailored for anab-interno procedure, which as previously mentioned, can be advantageousover the more invasive ab-externo approach. However, use of the ocularsystems in an ab-externo method may be contemplated in some instancesand thus, are not excluded here. The methods for delivering an oculardevice or fluid, or for providing a disruptive force, may be used totreat or prevent glaucoma, pre-glaucoma, or ocular hypertension. Whentreating glaucoma, the methods may also be used in conjunction with acataract surgery (before or after) using the same incision during thesame session or at another time.

Some of the methods, described in more detail below, may comprisedilating Schlemm's canal and/or aqueous collector channels (e.g., withviscoelastic fluid) using the delivery systems described herein. Othersof the methods, also described in more detail below, may comprisetearing or cutting the trabecular meshwork of Schlemm's canal. Thesemethods may be carried out separately, or they may be combined into asingle procedure. For example, in some instances a portion (e.g., half)of Schlemm's canal may be dilated (either using a fluid composition or atool, or both, for example), and the trabecular meshwork of the same ora different portion of Schlemm's canal may be torn or cut, within thesame eye. As another example, all of Schlemm's canal may be dilated, andthen all or a portion of the trabecular meshwork may subsequently betorn or cut. This may be desirable, for example, in order to both dilatethe collector channels and tear or cut the trabecular meshwork.

In some of these variations, dilation and tearing or cutting may beperformed using a single delivery system, such as one described hereinconfigured to deliver a fluid composition. For example, the elongatemember of a delivery system configured to deliver a fluid compositionmay first be used to deliver a fluid composition to a portion ofSchlemm's canal (e.g., about an 180 degree arc of the canal, about a 90degree arc of the canal) as described herein, and subsequently to tearor cut the trabecular meshwork in the same portion of the canal asdescribed herein. As another example, the elongate member of a deliverysystem configured to deliver a fluid composition may first be used todeliver a fluid composition to a portion of Schlemm's canal (e.g., aboutan 180 degree arc of the canal, about a 90 degree arc of the canal,etc.) and subsequently to tear or cut the trabecular meshwork in anotherportion of the canal (e.g., the other about-180 degree arc, another 90degree arc, etc.). As yet another example, the elongate member of adelivery system configured to deliver a fluid composition may first beused to deliver fluid composition to all of Schlemm's canal (e.g., bydelivering about 180 degrees of fluid composition in a first directionand then delivering about 180 degrees of fluid composition in a seconddirection), and then subsequently to tear or cut the full 360 degrees oftrabecular meshwork (e.g., by tearing or cutting about 180 degrees oftrabecular meshwork in a first direction and then tearing or cuttingabout 180 degrees of trabecular meshwork in a second direction).

In other variations, dilation and tearing or cutting may be performedusing different delivery systems (e.g., the dilation may be performedusing a delivery system configured to deliver a fluid composition, andthe tearing or cutting may be performed using a delivery system notconfigured to deliver a fluid). As yet another example, in someinstances dilation may be performed in one eye of a patient, while thetrabecular meshwork is torn or cut in the other eye of the patient.

Procedures dilating Schlemm's canal and/or tearing or cutting thetrabecular meshwork may also be combined with procedures delivering anocular device (described in more detail herein), either in the same eyeor in different eyes of the same patient. For example, all or a portionof Schlemm's canal may be dilated, followed by insertion of an oculardevice. As another example, a portion of the trabecular meshwork may betorn or cut, while an ocular implant may be delivered to another portionof Schlemm's canal. As yet another example, a portion of Schlemm's canalmay be dilated, while an ocular implant may be delivered to anotherportion of Schlemm's canal. As yet another example, an ocular implantmay be delivered to a portion of Schlemm's canal, and then Schlemm'scanal may be subsequently dilated to improve the function of the ocularimplant.

Ocular Device Delivery

In general, the methods for implanting an ocular device within Schlemm'scanal first include the step of creating an incision in the ocular wall(e.g., the sclera or cornea or corneoscleral limbus or junction) thatprovides access to the anterior chamber of the eye. As shown in thestylized depiction of an eye in FIG. 14, the cannula (1400) of theocular delivery system is then advanced through the incision and atleast partially across the anterior chamber (1402) to the trabecularmeshwork (not shown). Schlemm's canal (i.e., the lumen of Schlemm'scanal) (1404) is then accessed with the distal curved portion of thecannula (1406) and a slidable positioning element, (or, e.g., a slidabletool or guidewire), or elongate member (represented generically byelement 1408) is advanced from the cannula to implant an ocular devicewithin Schlemm's canal, perform a procedure within Schlemm's canal or onany of the neighboring trabeculocanalicular tissues, or deliver a fluidinto the canal. However, in some instances, a elongate member may not beemployed so that any fluid to be delivered is delivered through thecannula. In yet further variations, just the trabecular meshwork ispunctured and the fluid composition is delivered withoutcircumnavigation of Schlemm's canal.

As previously stated, in some variations the cannula may be configuredto include a proximal end and a distal curved portion, where the distalcurved portion has a proximal end, a distal end, and a radius ofcurvature defined between the ends. Here the cannula may also include abody and a distal tip having a bevel that directly engages the radius ofcurvature, e.g., it is contiguous with the radius of curvature. In othervariations, Schlemm's canal may be accessed with a straight cannula(i.e., one not having a distal curved portion). The method may alsoinclude the step of flushing the system with fluid (e.g., to remove airfrom the system) and/or the step of irrigating the operative field toclear away blood or otherwise improve visualization of the field.

Any suitable ocular device that maintains the patency of Schlemm's canalor improves outflow of aqueous humor may be implanted by the systemsdescribed herein. For example, ocular devices that maintain the patencyof Schlemm's canal without substantially interfering with fluid flowacross, along, or out of the canal may be implanted. Such devices maycomprise a support having at least one fenestration, as disclosed inU.S. Pat. Nos. 7,909,789, and 8,529,622, which were previouslyincorporated by reference in their entirety. Ocular devices that disruptthe juxtacanalicular trabecular meshwork or adjacent inner wall ofSchlemm's canal may also be implanted. In addition to ocular devicesmade from metal or metal alloys, the use of sutures, modified sutures,modified polymers, polymeric filaments, or solid viscoelastic structuresmay be delivered. Fluid compositions such as saline, viscoelasticfluids, air, drug mixtures or solutions, and gas may also be delivered.

When a fluid composition is delivered into Schlemm's canal, the methodsgenerally include the steps of creating an incision in the ocular wall(e.g., the sclera or cornea) that provides access to the anteriorchamber of the eye; advancing a cannula of the ocular delivery systemthrough the incision and at least partially across the anterior chamberto the trabecular meshwork; accessing Schlemm's canal with the cannula;and delivering the fluid composition into the canal using a elongatemember slidable within the cannula lumen. The cannula may be configuredto include a proximal end and a distal curved portion, where the distalcurved portion has a proximal end, a distal end, and a radius ofcurvature defined between the ends. Here the cannula may also include abody and a distal tip having a bevel that directly engages the radius ofcurvature, e.g., it is contiguous with the radius of curvature. Furtheradvantageous cannula features may also be included, which are describedabove. The method may also include the step of flushing the system withfluid (e.g., to remove air from the system) and/or the step ofirrigating the operative field to clear away blood or otherwise improvevisualization of the field.

When an ab-interno method is employed for implanting an ocular device,the method may include the following steps. The surgeon may first viewthe anterior chamber and trabecular meshwork (with underlying Schlemm'scanal) using an operating microscope and a gonioscope or gonioprism.Using a 0.5 mm or greater corneal, limbal, or sclera incision, thesurgeon may then gain access to the anterior chamber. A saline solutionor viscoelastic composition may then be introduced into the anteriorchamber to prevent its collapse. Here the saline solution orviscoelastic composition may be delivered through the delivery systemcannula or by another mode, e.g., by infusion through an irrigatingsleeve on the cannula. The surgeon, under direct microscopicvisualization, may then advance the cannula of the delivery systemthrough the incision towards the anterior chamber angle. When nearingthe angle (and thus the trabecular meshwork), the surgeon may apply agonioscope or gonioprism to the cornea to visualize the angle. Theapplication of a fluid (e.g., a viscous solution or a viscoelasticcomposition as previously described) to the cornea and/or gonioscope orgonioprism may help to achieve good optical contact and negate totalinternal reflection thereby allowing visualization of the anteriorchamber angle. As the surgeon visualizes the trabecular meshwork, thecannula may then be advanced so that the bevel of at the distal end ofthe curved distal portion of the cannula pierces the meshwork and is incommunication with the lumen of Schlemm's canal. The surgeon mayirrigate saline or a viscoelastic composition into the canal or into theanterior chamber to either prevent collapse of chamber, dilate Schlemm'scanal, or wash away any blood that may obscure visualization of cannulaand ocular device delivery. Next, when the ocular device is advanced tothe extent desired by the surgeon, it is released from the engagementmechanism so that it can reside in Schlemm's canal. If repositioning ofthe ocular device is needed or desired, the surgeon may retract and/orreposition the ocular device using the positioning element of thedelivery system. The surgeon may then withdraw the delivery system fromthe eye.

Other variations of the ab-interno method for implanting an oculardevice include the use of an endoscope. Similar to the method above,access to the anterior chamber is first made by incising the cornea,limbus, or sclera. Again, this may be done in combination with cataractsurgery in one sitting, either before or after cataract surgery, orindependently. The anterior chamber may be infused with saline solutionor a viscoelastic composition may be placed in the anterior chamber toprevent its collapse. The saline or viscoelastic may be delivered as aseparate step or it may be infused with the elongate member of thedelivery system, an irrigating sleeve on the elongate member or cannula,or with a separate infusion cannula. The surgeon, under directmicroscopic visualization, then advances the endoscope through theincision and towards the angle and trabecular meshwork. As the surgeonvisualizes the trabecular meshwork using the endoscope or any associatedvideo display, the bevel of the cannula is advanced to pierce themeshwork. The ocular device is then advanced using the positioningelement under endoscopic visualization. The surgeon may irrigate salineor a viscoelastic composition into the canal or into the anteriorchamber to either prevent collapse of chamber, dilate Schlemm's canal,or wash away any blood that may obscure visualization of cannula andocular device delivery. When the ocular device is advanced to the extentdesired by the surgeon, it is released from the engagement mechanism sothat it can reside in Schlemm's canal. If repositioning of the oculardevice is needed or desired, the surgeon may retract and/or advance theocular device using the positioning element of the delivery system. Thesurgeon may then withdraw the delivery system from the eye.

Fluid Composition Delivery

Some methods described herein may comprise delivering fluid compositioninto the eye, such as into Schlemm's canal. In some methods, an elongatemember comprising a lumen may be advanced into Schlemm's canal and thefluid composition may be delivered via the elongate member. Both theelongate member and fluid delivery may dilate Schlemm's canal, and fluiddelivery may additionally dilate the collector channels. With respect tothe delivery of a fluid composition, the methods are similar to theimplantation of an ocular device. However, instead of using apositioning element, the delivery system may employ a slidable elongatemember to infuse a fluid composition into Schlemm's canal.

The fluid compositions may be delivered to dilate Schlemm's canal. Theentire length of Schlemm's canal or a portion thereof may be dilated bythe fluid. For example, at least 75%, at least 50%, at least 25%, atleast 10% of the canal, or at least 1% of the canal may be dilated. Thefluid compositions may also be delivered to treat various medicalconditions of the eye, including but not limited to, glaucoma,pre-glaucoma, anterior or posterior segment neovascularization diseases,anterior or posterior segment inflammatory diseases, ocularhypertension, uveitis, age-related macular degeneration, diabeticretinopathy, genetic eye disorders, complications of cataract surgery,vascular occlusions, vascular disease, or inflammatory disease.

The surgeon may first view the anterior chamber and trabecular meshwork(with underlying Schlemm's canal) using an operating microscope and agonioscope or gonioprism. Using a 0.5 mm or greater corneal, limbal, orsclera incision, the surgeon may then gain access to the anteriorchamber. A saline solution or viscoelastic composition may then beintroduced into the anterior chamber to prevent its collapse. Here thesaline solution or viscoelastic composition may be delivered through thedelivery system cannula or by another mode, e.g., by infusion through anirrigating sleeve on the cannula. The surgeon, under direct microscopicvisualization, may then advance the cannula of the delivery systemthrough the incision towards the anterior chamber angle. When nearingthe angle (and thus the trabecular meshwork), the surgeon may apply agonioscope or gonioprism to the cornea to visualize the angle. Theapplication of a viscous fluid (e.g., a viscoelastic composition aspreviously described) to the cornea and/or gonioscope or gonioprism mayhelp to achieve good optical contact and negate total internalreflection thereby allowing visualization of the anterior chamber angle.As the surgeon visualizes the trabecular meshwork, the cannula may thenbe advanced so that the bevel of at the distal end of the curved distalportion of the cannula pierces the meshwork and is in communication withthe lumen of Schlemm's canal.

Next, a slidable elongate member coaxially disposed within the cannulalumen may be advanced into the canal under gonioscopic visualization.The elongate member may be advanced any suitable amount and directionabout the canal. For example, the elongate member may be advancedbetween about 1 degree and about 360 degrees about the canal, betweenabout 10 degrees and about 360 degrees about the canal, between about150 and about 210 degrees about the canal, or any suitable distance,about 360 degrees about the canal, about 270 degrees about the canal,about 180 degrees about the canal, about 120 degrees about the canal,about 90 degrees about the canal, about 60 degrees about the canal,about 30 degrees about the canal, or about 5 degrees about the canal. Insome variations, the elongate member may be advanced in two steps, e.g.,first in a clockwise direction (e.g., about 180 degrees, about 90degrees, etc.) and second in a counterclockwise direction (e.g., about180 degrees, about 90 degrees, etc.) about the canal (e.g., to therebyachieve a 360 or 180 degree ab-interno viscocanalostomy orcanaloplasty). Fluid may be injected upon advancement or retraction ofthe elongate member. Once the slidable elongate member has beenpositioned within the canal, a fluid composition, e.g., a viscoelasticsolution, may be continuously or intermittently delivered through thelumen of the elongate member. The fluid composition may exit the lumenof the elongate member through its distal end (e.g., the through thedistal tip), or through openings or fenestrations provided along itsshaft, or a combination of both. The openings or fenestrations may bespaced along the axial length of the elongate member in any suitablemanner, e.g., symmetrically or asymmetrically along its length. Othersubstances such as drugs, air, or gas may delivered be in the samemanner if desired.

In some variations, the slidable elongate member may be repositioned byretraction or repeated advancement and retraction. In some variations ofthe method, the same or different incision may be used, but the deliverysystem cannula is employed to access and dilate Schlemm's canal from adifferent direction (e.g., counterclockwise instead of clockwise). Oncea sufficient amount of fluid has been delivered, the surgeon may retractthe slidable elongate member into the cannula and remove the deliverysystem from the eye. It should be appreciated that the cannulasdescribed here may be specifically manufactured to comprise adual-surface configuration at the distal tip (i.e., sharp and smoothsurfaces), which may allow the elongate member to be advanced,repositioned, and/or retracted without severing it on the distal tip ofthe cannula. It should also be understood that these steps may be usedalone or in combination with cataract surgery (in one sitting).

Some of the delivery systems described herein may be configured suchthat the cumulative amount of advancement and/or retraction of theslidable elongate member is limited. For example, as described above,after the elongate member is advanced and retracted a particularcumulative distance (e.g., about 39 mm to about 40 mm each ofadvancement and retraction, corresponding to the approximatecircumference of Schlemm's canal; or about 78 mm to about 80 mm each ofadvancement and retraction, corresponding to approximately twice thecircumference of Schlemm's canal; or any other suitable distance), itmay no longer be able to be advanced. This advancement and retractionmay occur over multiple advancement-retraction cycles. For example, theelongate member may be advanced about 20 mm, then retracted by about 20mm, then advanced by about 20 mm, then retracted by about 20 mm. Whenthe cumulative distance is limited to about 40 mm, after these twocycles of advancement and retraction, the elongate member may no longerbe able to be advanced.

In some variations of the ab-interno method, the fluid composition maybe delivered simultaneously with retraction of the elongate member(i.e., the fluid compositions may be delivered in a manner whereretraction of a system component allows advancement of the fluid out ofthe system cannula). Referring again to FIGS. 11A-11C, linear gear(1108) is retracted in the direction of the arrow (FIG. 11B) so thatreservoir (1102) becomes pressurized. Retraction can be accomplished byrotation of pinion gear mechanisms (1120). Once a sufficient amount ofpressure has been created in the reservoir (1102) the fluid compositioncontained therein is injected through linear gear lumen (1114) andelongate member (1118) into Schlemm's canal. It should be understoodthat the ocular delivery systems may be configured so that the fluidcompositions are delivered continuously, passively, automatically, oractively by the surgeon. The fluid compositions may also be delivered tothe canal independent of the gear shaft movement with a pump orauxiliary plunger. In some variations, retraction of the elongate membermay correspond to a fixed volume of fluid composition being deliveredvia the lumen of the elongate member. The fluid composition may bedelivered via the distal opening of the lumen of the elongate member asit is retracted, and thus, the fluid may be evenly delivered throughoutthe portion of the canal through which the elongate member was advanced.

The fluid compositions that may be delivered by the ocular systemsdescribed herein include but are not limited to saline and viscoelasticfluids. The viscoelastic fluids may comprise hyaluronic acid,chondroitin sulfate, cellulose, derivatives or mixtures thereof, orsolutions thereof. In one variation, the viscoelastic fluid comprisessodium hyaluronate. In another variation, the viscoelastic compositionmay further include a drug. For example, the viscoelastic compositionmay include a drug suitable for treating glaucoma, reducing or loweringintraocular pressure, reducing inflammation, fibrosis neovascularizationor scarring, and/or preventing infection. The viscoelastic compositionmay also include agents that aid with visualization of the viscoelasticcomposition. For example, dyes such as but not limited to fluorescein,trypan blue, or indocyanine green may be included. In some variations, afluorescent compound or bioluminescent compound is included in theviscoelastic composition to help with its visualization. In othervariations, the system delivers the drug alone, without the viscoelasticcomposition. In this case, the drug may be loaded onto or into asustained release biodegradable polymer that elutes drug over a periodof weeks, months, or years. It is also contemplated that air or a gascould be delivered with the systems, as described herein.

Other variations of the ab-interno method for delivering a fluidcomposition include the use of an endoscope. Similar to the methoddescribed directly above, access to the anterior chamber is first madeby incising the cornea, limbus, or sclera. Again, this may be done incombination with cataract surgery in one sitting, either before or aftercataract surgery, or independently. The anterior chamber may be infusedwith saline solution or a viscoelastic composition may be placed in theanterior chamber to prevent its collapse. The saline or viscoelastic maybe delivered as a separate step or it may be infused with the elongatemember of the delivery system, an irrigating sleeve on the elongatemember or cannula, or with a separate infusion cannula. The surgeon,under direct microscopic visualization, then advances the endoscopethrough the incision and towards the angle and trabecular meshwork. Asthe surgeon visualizes the trabecular meshwork via the endoscope or anyassociated display, the bevel of the cannula is advanced to pierce themeshwork. The elongate member is then advanced under endoscopicvisualization. The elongate member may be advanced any suitable amountand direction about the canal. For example, the elongate member may beadvanced between about 10 degrees to about 360 degrees about the canal,or it may be advanced in two steps, e.g., 180 degrees in a clockwisedirection and 180 degrees in a counterclockwise direction about thecanal (to thereby achieve a full 360 degree ab-internoviscocanalostomy). Once the elongate member has been positioned withinthe canal, a fluid composition, e.g., a viscoelastic fluid, may becontinuously or intermittently delivered through the lumen of theelongate member. The fluid composition may exit the lumen of theelongate member through its distal end (e.g., the through the distaltip), or through openings or fenestrations provided along its shaft, ora combination of both. The openings or fenestrations may be spaced alongthe axial length of the elongate member in any suitable manner, e.g.,symmetrically or asymmetrically along its length. Other substances suchas drugs, air, or gas may be delivered in the same manner if desired.The elongate member may be repositioned by retraction or repeatedadvancement and retraction. In some variations of the method, the sameor different incision may be used, but the delivery system cannula isemployed to access and dilate Schlemm's canal from a different direction(e.g., counterclockwise instead of clockwise). Once a sufficient amountof fluid has been delivered, the surgeon may retract the slidableelongate member into the cannula and remove the delivery system from theeye.

One variation of the methods described here is illustrated in FIGS.28A-D, and may be carried out using a delivery system as described withrespect to FIGS. 23A-23F. FIG. 28A shows a flow chart illustrating themethod. The method shown there may allow for single-handed, manuallyoperated delivery of fluid (e.g., viscoelastic fluid or gel) intoSchlemm's canal via a slidable elongate member comprising a lumen (e.g.,a microcatheter). The delivery of viscoelastic fluid may be metered,such that controlled, small amounts of viscoelastic can be delivered tothe eye. The method may allow for catheterization and transluminalviscodilation of 360 degrees of Schlemm's canal using a single clearcorneal incision for access. This may, for example, reduce intraocularpressure in patients with glaucoma (e.g., open-angle glaucoma).

First, the delivery system may be removed from its packaging. Next, thedelivery system may be pre-loaded with viscoelastic fluid. A loadingtool (e.g., a nozzle), which may be supplied with the delivery system ina kit, may be attached to a viscoelastic cartridge. Suitablecommercially available viscoelastics include but are not limited toHealon™, HealonGV™, Amvisc™, and PROVISC™. The loading tool may then beflushed with viscoelastic. The lock on the proximal end of the deliverysystem may then be rotated (while remaining attached to the handle ofthe device device) to expose a proximal opening in the device. Thenozzle may then be inserted into the proximal opening and viscoelasticfluid injected from the viscoelastic cartridge into the reservoir of thedelivery system. It may be desirable to hold the delivery system andviscoelastic cartridge upright during injection. The viscoelastic fluidmay be injected until viscoelastic flow from the distal tip of thecannula is visualized. The lock may then be removed from the deliverysystem.

To deliver viscoelastic fluid into the eye, the cannula may be advancedinto the anterior chamber through an existing corneal or scleralincision. It may be desirable for the incision to be at least about 1 mmwide. The distal tip of the cannula may be used to pierce the trabecularmeshwork to enter Schlemm's canal. The cannula may be held securelyagainst the angle while the elongate member is advanced into Schlemm'scanal. An exposed portion of one or more of the wheels of the driveassembly may be rotated proximally to advance the elongate member up toabout 180 degrees around Schlemm's canal (about 18 mm, about 19 mm,about 20 mm, about 18 mm to about 20 mm, or about 15 mm to about 25 mmof circumferential canal travel). At this point, the elongate member maybe fully extended, and the wheel may no longer be able to be rotated.During this procedure, direct microscopic or gonioscopic visualizationof the cannula tip may be maintained, and the anterior chamber may bemaintained with viscoelastic or continuous balanced salt solutioninfusion.

One or more wheels may then be rotated distally to retract the elongatemember. As the elongate member is retracted, a specific predeterminedvolume of viscoelastic may be steadily delivered out of the lumen of theelongate member in a metered fashion, which may cause transluminalviscodilation of Schlemm's canal and/or collector channels. In somevariations, full retraction of the elongate member results in thedelivery of between about 2 μl and about 9 μl of viscoelastic fluid(e.g., about 4.5 μl of viscoelastic fluid). The wheels may be configuredto be incrementally rotated with audible and/or tactile clicks atincremental rotation; in some cases, about 0.5 μl of viscoelastic fluidmay be delivered with each click. The delivery of viscoelastic (2800) toSchlemm's canal (2802) and collector channels (2804) during retractionof the elongate member (2806) into the cannula (2808) is shown in FIGS.28B-28D. As can be seen in FIGS. 28C-28D, the angle and length ofdelivery of viscoelastic (2800) to Schlemm's canal corresponds to theangle and length of advancement of the elongate member into the canal.In some instances, viscoelastic may be used to tamponade any bloodreflux back into the anterior chamber.

Viscoelastic may then optionally be delivered to the other half ofSchlemm's canal. The cannula tip may be removed from Schlemm's canal andthe delivery system may be flipped, such that the cannula tip is rotated180 degrees to face the opposite direction. In some instances, thedelivery system may be flipped in the anterior chamber, without removingthe cannula from the eye. In other instances, the delivery system may beremoved from the eye, flipped, and reinserted into the incision. Thecannula tip may then be reinserted into Schlemm's canal via the sameincision in the trabecular meshwork, and advancement, retraction, anddelivery of viscoelastic fluid as described above may be repeated toviscodilate the remaining 180 degrees of Schlemm's canal. The completeprocedure may deliver between about 4 μl and about 18 μl of viscoelasticfluid in total to the eye (e.g., about 9 μl of viscoelastic fluid).

At the end of the procedure, the anterior chamber may be irrigated(e.g., with balanced salt solution) through the corneal wound (eithermanually or automated). A balanced salt solution or viscoelastic may beused to reform the anterior chamber as needed to achieve physiologicpressure and further tamponade any blood reflux from the collectorchannels back into the anterior chamber. If necessary, a suture may beused to seal the corneal or scleral incision. Postoperatively, anantibiotic or antiseptic, mydriatic agent, or a miotic agent, may beused as appropriate. For example, a miotic eye drop may be used forweeks or months to help prevent synechiae formation and angle closure.

More generally, in methods described herein, exemplary volumes ofviscoelastic fluid that may be delivered may in some instances bebetween about 1 μl and about 200 μl, or in some instances be betweenabout 1 μl and about 100 μl. In some instances, sufficient volumes toprovide a disruptive force may range from about 1 μl to about 50 μl,from about 1 μl to about 30 μl, or from about 2 μl to about 16 μl. Inone variation, a volume of about 4 μl is sufficient to disrupt Schlemm'scanal and/or the surrounding tissues. In other variations, the volume ofviscoelastic fluid sufficient to disrupt trabeculocanalicular tissuesmay be about 2 μl, about 3 μl, about 4 μl, about 5 μl, about 6 μl, about7 μl, about 8 μl, about 9 μl, about 10 μl, about 11 μl, about 12 μl,about 13 μl, about 14 μl, about 15 μl, about 16 μl, about 17 μl, about18 μl, about 19 μl, about 20 μl, about 25 μl, about 30 μl, about 35 μl,about 40 μl, about 45 μl, or about 50 μl.

Tissue disruption may occur by viscodilating excessively andintentionally with at least about 1 μl, at least about 2 μl, at leastabout 3 μl, at least about 4 μl, at least about 5 μl, at least about 6μl, at least about 7 μl, at least about 8 μl, at least about 9 μl, atleast about 10 μl, at least about 11 μl, at least about 12 μl, at leastabout 13 μl, at least about 14 μl, at least about 15 μl, at least about16 μl, at least about 17 μl, at least about 18 μl, at least about 19 μl,or at least about 20 μl of viscoelastic fluid per 360 degree arc of thecanal. In some variations, at least about 20 μl, at least about 25 μl,at least about 30 μl, at least about 35 μl, at least about 40 μl, atleast about 45 μl, or at least about 50 μl of viscoelastic fluid may bedelivered.

Depending on factors such as the type or severity of the condition beingtreated, the disruptive force may be generated to partially orcompletely destroy and/or remove the trabecular meshwork, and may beadjusted by varying the volume of viscoelastic fluid delivered. Forexample, 8 μl may be used to perforate or gently tear the meshwork,while 16 μl may be used to maximally cut or tear the meshwork. Morespecifically, about 1 to 2 μl may be used to dilate Schlemm's canal andcollector channels; about 2 to 4 μl may be used to dilate Schlemm'scanal and collector channels, and stretch juxtacanalicular tissues; andabout 4 to 6 μl may be used for all the foregoing and for the creationof microtears or microperforations in the trabecular meshwork andjuxtacanalicular tissues (further increasing porosity and outflow). Avolume of about 8 to 16 μl may be used for all the foregoing and forsubstantial perforation/tearing of the trabecular meshwork andjuxtacanalicular tissues. A volume of about 16 to 50 μl may be used forsubstantial or complete tearing or cutting of the trabecular meshwork.

The total volume of viscoelastic fluid may be delivered along a 360degree arc (1600) of Schlemm's canal during a single advancement from asingle access point (1602) in the canal (e.g., as shown in FIG. 16) orwithdrawal of the elongate member (1604), or along lesser degrees of arcin multiple advancements or withdrawals of the elongate member. Forexample, as shown in FIG. 17, a elongate member (1700) may be advancedalong a 180 degree arc of the canal in both clockwise (1702) andcounterclockwise (1704) directions to deliver fluid from, e.g., a singleaccess point (1706) in the canal. Referring to FIGS. 16 and 17, anexemplary disruptive volume of between about 4 μl and about 18 μl may bedelivered along a 360 degree arc of the canal while the elongate memberis advanced from a single access point in the canal, or between about 2μl and about 9 μl may be delivered along a 180 degree arc of the canalduring two advancements (one in the clockwise direction and the other inthe counterclockwise direction) of the elongate member from a singleaccess point in the canal. More specifically, an exemplary disruptivevolume may be about 9 μl delivered along a 360 degree arc of the canal,or about 4.5 μl delivered along a 180 degree arc of the canal duringeach of two advancements. The elongate member may access the canal froma single point or from multiple points.

Additionally, the fluid compositions may be delivered to restore thetubular anatomy of Schlemm's canal, to clear obstructions within thecanal, to disrupt juxtacanalicular trabecular meshwork or the inner wallof Schlemm's canal within the canal, or to expand the canal. Here thedelivery systems may include wires, tubes, balloons, instruments thatdeliver energy to the tissues, and/or other features to help with thesemethods. It is contemplated that glaucoma may be treated using suchsystems with additional features. The surface of these systems may alsobe roughened or have projections to further disrupt the inner wall ofSchlemm's canal and juxtacanalicular trabecular meshwork to enhanceaqueous humor outflow or permeability.

The viscoelastic fluid may be delivered while advancing the elongatemember of a single-handed, single-operator controlled device fromSchlemm's canal in the clockwise direction, counterclockwise direction,or both, or during withdrawal of the elongate member from Schlemm'scanal. As previously stated, the viscoelastic fluid may be delivered todisrupt Schlemm's canal and surrounding trabeculocanalicular tissues.For example, the delivered viscoelastic fluid may cause disruption bydilating Schlemm's canal, increasing the porosity of the trabecularmeshwork, stretching the trabecular meshwork, forming microtears orperforations in juxtacanalicular tissue, removing septae from Schlemm'scanal, dilating collector channels, or a combination thereof. Theelongate member may be loaded with the viscoelastic fluid at the startof an ocular procedure so that the fluid can be delivered by a singledevice. This is in contrast to other systems that use forceps or otheradvancement tool to advance a fluid delivery catheter into Schlemm'scanal and/or devices containing viscoelastic fluid that are separate orindependent from a delivery catheter or catheter advancement tool, andwhich require connection to the delivery catheter or catheteradvancement tool during a procedure by an assistant while the deliverycatheter or catheter advancement tool is held by the surgeon.

Tool Delivery

Prior to the introduction of goniotomy and trabeculotomy (both of whichare typically used to treat an obstructed trabecular meshwork, oftengenetically-driven at a young age), congenital glaucoma uniformlyresulted in blindness. Despite the invasiveness of goniotomy (which isperformed ab-interno, but a sharp scalpel is used to cut 30-60 degreesof meshwork to improve outflow) and trabeculotomy (ab-externo methodwhere deep scleral incisions unroof Schlemm's canal and the meshwork iscut with a probe), the procedures are viewed as being effective and haveallowed many pediatric patients to possibly avoid an entire lifetime ofblindness. In 1960, Burian and Smith each independently describedtrabeculotomy ab-externo. In this highly invasive ab-externo operation,the surgeon makes a deep scleral incision, finds Schlemm's canal,cannulates all 360 degrees of Schlemm's canal externally with a catheteror specially designed probe called a trabeculotome, and finally tensionsboth ends of the catheter or probe to the point where the trabeculotomecuts through the entire trabecular meshwork into the anterior chamber toimprove drainage.

More recent attempts at decreasing the invasiveness of ab-externotrabeculotomy have been developed by NeoMedix, which commercializes adevice called “Trabectome.” The Trabectome attempts to maketrabeculotomy easier by using an ab-interno approach. The instrument andmethods involve removal of the trabecular meshwork ab-interno byelectrocautery using an instrument that also provides infusion andaspiration. The disadvantages of the Trabectome are three-fold: 1) thedevice employs an energy-based mechanism to ablate trabecular meshwork,which is believed to cause inflammation and scarring in the eye, whichin turn can adversely impact outflow and pressure; 2) thedevice/procedure is ergonomically limited—it requires a foot pedal andpower cords to activate electrocautery and irrigation in addition tobeing limited to 60-120 degrees of meshwork therapy per corneal orscleral entry incision; and 3) because it involves energy-based ablationand irrigation, there is capital equipment required.

The methods (as well as systems and devices) described herein, includingthe method for providing a disruptive force to trabeculocanaliculartissues, may be highly suitable for ab-interno trabeculotomy andgoniotomy given that they avoid the use of electrocautery, and arecapable of advancing elongate members over larger degrees of arc ofSchlemm's canal. When the systems and devices are tailored to provide adisruptive force to the trabeculocanalicular tissues, implant-freemethods may be employed, e.g., by delivering a disruptive volume ofviscoelastic fluid, advancing disruptive tools, e.g., cannulas, elongatemembers, catheters, etc., or both. In some instances, disruptive toolsmay comprise disruptive components on their distal portions. Exemplarydisruptive components include, without limitation, notches, hooks,barbs, balloons, or combinations thereof. In other instances, thedisruptive tools may not comprise disruptive components on their distalportions, and indeed may have atraumatic blunt distal portions.Exemplary atraumatic distal portions include, without limitation,parasol or dome shaped distal portions.

In some variations of the ab-interno trabeculotomy and goniotomymethods, the procedure includes advancing a cannula at least partiallythrough the anterior chamber of the eye, entering Schlemm's canal at asingle access point using the cannula, and delivering a volume of aviscoelastic fluid through a elongate member comprising a lumen andslidable within, and extendable from, the cannula, sufficient to disruptthe structure of Schlemm's canal and surrounding tissues to reduceintraocular pressure. Other methods that may be useful in treatingconditions of the eye include the steps of entering Schlemm's canalusing a elongate member extendable from a single-operator controlledhandle, the handle comprising a fluid reservoir, and delivering a volumeof a viscoelastic fluid from the fluid reservoir through the elongatemember by increasing pressure within the fluid reservoir, where thevolume of delivered viscoelastic fluid is sufficient to disrupt thestructure of Schlemm's canal and surrounding tissues to reduceintraocular pressure. The disruptive volume may be between about 2 μl toabout 16 μl. In one variation, the disruptive volume is about 4 μl ofviscoelastic fluid. As previously stated, in some instances thedisruptive volume may range anywhere between about 20 μl to about 50Methods based on fluid delivery are described in more detail above.

When fluids are not used, and only a disruptive tool is employed, theouter diameter of the elongate member or tool may be variously sized fordisruption of tissues, analogous to how fluid volumes may be varied tovary the level of disruption. For example, an elongate member or toolhaving an outer diameter ranging from about 50 to about 100 microns maybe advanced through the canal to slightly dilate the canal and break orremove septae obstructing circumferential canalicular flow. An elongatemember or tool having an outer diameter ranging from about 100 to 200microns may be employed to perform the foregoing, and may also to beginto stretch the trabecular meshwork and juxtacanalicular tissues. Anelongate member or tool having an outer diameter ranging from about 200to about 300 microns may be able to perform the above, but may alsocreate microtears in the trabecular meshwork and juxtacanaliculartissues, and may maximally dilate the collector channels. An elongatemember or tool having an outer diameter ranging from about 300 to about500 microns may maximally disrupt the tissues and may create tears orperforations all along the trabecular meshwork and juxtacanaliculartissues. Additionally, the further the advancement of the elongatemember or tool through the canal, the greater the efficacy of theprocedure. For example, the elongate member or tool may be advanced outfrom the tip of the cannula and into the canal about a 30 degree arc ofthe canal (e.g., advanced about 3 to 4 mm out of the cannula), advancedabout a 60 degree arc of the canal (e.g., advanced about 6 to 8 mm outof the cannula), advanced about a 90 degree arc of the canal (e.g.,advanced about 10 mm out of the cannula), advanced about a 120 arc ofthe canal (e.g., advanced about 15 mm out of the cannula), advancedabout a 180 degree arc of the canal (e.g., advanced about 20 mm out ofthe cannula), or advanced about a full 360 degrees of the canal (e.g.,advanced about 36 to 40 mm out of the cannula), for maximal efficacy andmaximal intraocular pressure reduction. In some variations, the elongatemember may have a non-uniform outer diameter. For example, the elongatemember may have a tapered outer diameter, such that the outer diameterincreases from the distal to proximal end.

In some variations, the methods disclosed herein may include advancementof the elongate member (or a tool) between about a 5 degree arc ofSchlemm's canal and about a 360 degree arc. In some variations, themethods may include advancement of the elongate member (or tool) about a360 degree arc of Schlemm's canal, about a 270 degree arc of Schlemm'scanal, about a 120 degree arc of Schlemm's canal, about a 180 degree arcof Schlemm's canal, or about a 90 degree arc of Schlemm's canal. In yetfurther variations, advancement of the elongate member (or a tool) maybe about a 0 to 5 degree arc of Schlemm's canal, about a 30 degree arcof Schlemm's canal, or about a 60 degree arc of Schlemm's canal.Advancement may occur from a single access point in Schlemm's canal orfrom multiple access points in the canal. When a disruptive force is tobe provided, it may be beneficial to advance the elongate member in bothclockwise and counterclockwise directions about a 180 degree arc ofSchlemm's canal from a single access point in the canal.

Depending on factors such as the type or severity of the condition beingtreated, the disruptive force may be generated to partially orcompletely destroy and/or remove the trabecular meshwork, and may beadjusted by varying the tool configuration. In some methods, thetrabecular meshwork may be disrupted during advancement of the slidableelongate member. Customizing a body segment of the elongate memberproximal to the tip with one or more notches, barbs, or balloons thatcatch the meshwork as the distal tip is being guided and advanced alongSchlemm's canal could also be used, thereby disrupting, partiallytearing, fully tearing, and/or removing trabecular meshwork uponadvancement. Additionally, an implant with edges specifically designedto cut the meshwork could be used.

In yet other methods, the trabecular meshwork may be disrupted duringretraction of the slidable elongate member. Still other methods fordisrupting tissues may involve customizing the system (e.g., theelongate member, any catheters or wires, probe tips, etc.) to catch orgrasp the meshwork upon retraction after complete advancement throughthe canal. This may be done using a wire with a bent tip, hook, notch,or barb on its end that is advanced through the lumen of the catheterthat then snags the meshwork upon retraction, tearing it along itslength or removing it altogether, or solely with a metal or polymer wireor suture (no catheter) whose tip (and/or body) is hooked, notched, orbarbed in such a way that it can be advanced into Schlemm's canalwithout tearing the meshwork but snags the meshwork upon retraction,tearing the meshwork and/or removing it completely. Alternatively, asshown in FIG. 18C, the elongate member (1806) may be provided with adisruptive tool, e.g., a sharp-edged element (1808), that can cut ortear the trabecular meshwork while being retracted into the cannula(1800), which is held stationary. Exemplary sharp-edged elements may bea hook, wire, or any other suitable shape memory component that canextend from the cannula to tear, cut, or remove trabecular meshwork.

Another method for disrupting tissues may include using oversizedelongate members (e.g., having an outside diameter of 300-500 microns)to tear the meshwork upon delivery, or inflating or expanding theelongate member once it has been fully advanced into Schlemm's canal tostretch, disrupt, rupture, or fully tear the meshwork. For example, acatheter/elongate member, probe, or wire (with or without a lumen) whosetip is 200-250 microns in outer diameter, but having a shaft that beginsto flare outwards after 3 clock hours of Schlemm's canal (i.e., at aboutthe 5 or 10 mm mark on the catheter/elongate member) up to about 300, upto about 400, or up to about 500 microns, may be used, so that as thetip advances comfortably within Schlemm's canal, the enlarged shafttrails behind and ruptures the trabecular meshwork as it is advanced.

In another method, cutting, destruction, removal, or the like of thetrabecular meshwork may be accomplished by removing the cannula from theeye while leaving the elongate member in the canal, thereby tearingthrough the meshwork. Referring to FIG. 18A, a cannula (1800) may beinserted into the anterior chamber (1802) and Schlemm's canal (1804),and a tool (e.g., a slidable elongate member (1806)) may be advancedwithin the canal (1804). As shown in FIG. 18B, the cannula (1800) can beremoved from the anterior chamber (1802) without retracting the elongatemember (1806). This action by itself may tear the trabecular meshwork.As the cannula (1800) is removed from the anterior chamber (1802), theelongate member (1806) may begin tearing the trabecular meshwork fromthe point at which the cannula (1800) was inserted into Schlemm's canal(1804), and may continue tearing around the trabecular meshwork towardthe distal end of the elongate member.

A variation of the methods described here is illustrated in FIGS.29A-29D, and may be carried out using a delivery system such as onedescribed with respect to FIGS. 23A-23F. FIG. 29A shows a flow chartillustrating the method. The method may be used to access the trabecularoutflow system using a single clear corneal incision, and may allow fortransluminal trabeculotomy of up to 360 degrees. The method may use aflexible elongate member that may be advanced and retracted using asingle-handed disposable manual instrument. First, the device may beremoved from its packaging. The lock may then be removed from thedelivery system. The cannula may be advanced into the anterior chamberthrough an existing corneal or scleral incision. It may be desirable forthe incision to be at least about 1 mm wide. The distal tip of thecannula may be used to pierce the trabecular meshwork to enter Schlemm'scanal. The cannula may be held securely against the angle while theflexible elongate member is advanced into Schlemm's canal. An exposedportion of one or more of the wheels may be rotated proximally toadvance the flexible elongate member up to about 180 degrees aroundSchlemm's canal (about 20 mm of circumferential canal travel). At thispoint, the flexible elongate member may be fully extended, and the wheelmay no longer be able to be rotated. During this procedure, directmicroscopic or gonioscopic visualization of the cannula tip may bemaintained, and the anterior chamber may be maintained with viscoelasticor continuous balanced salt solution infusion.

Once the flexible elongate member is advanced, the cannula may beremoved from the eye through the incision without retracting theflexible elongate member. This may cause the flexible elongate member tocut through the trabecular meshwork. In some instances, it may bedesirable to bias the distal tip of the cannula toward the trabecularmeshwork being cut; this may in some instances help to prevent theflexible elongate member from slipping out of the canal during cannularemoval. Removal of the cannula (2900) without retraction of theflexible elongate member (2902) to tear the trabecular meshwork (2904)is illustrated in FIGS. 29B-29D. As can be seen there, the elongatemember (2902) transmits the force from removing the cannula (2900) intoa force that tears the trabecular meshwork. Removal of the cannula(2900) results in an “unzipping” effect to tear the trabecular meshwork.That is, the trabecular meshwork is torn by the body of the elongatemember (2902) from its proximal to distal end. First, force on thetrabecular meshwork from the proximal end of the body of the elongatemember (2902) causes the trabecular meshwork to tear near the insertionpoint of the cannula (2900). As the cannula (2900) continues to bewithdrawn from the eye, as shown in FIGS. 29C and 29D, the body of theelongate member (2902) continues to tear through the trabecularmeshwork, toward the distal tip of the elongate member. It should benoted that this method causes the trabecular meshwork to beprogressively torn from a first location (the proximal end of theextended elongate member, near the insertion point of the cannula) to asecond location (the distal end of the extended elongate member), asopposed to being cut or torn simultaneously along the distance from thefirst location to the second location. Furthermore, it should be notedthat in this method each portion of the trabecular meshwork is not tornby a single feature of the elongate member (e.g., a distal end of theelongate member upon advancement or retraction); rather, each portion ofthe trabecular meshwork is torn by the portion of the elongate memberadjacent to it after the elongate member has been advanced.

After the delivery system is fully removed from the eye, the flexibleelongate member may be retracted back into the cannula by rotating oneor more of the wheels distally. Once the flexible elongate member isfully retracted, the delivery system may be flipped, such that thecannula tip is rotated 180 degrees to face the opposite direction. Thecannula tip may then be advanced into the anterior chamber through thecorneal or scleral incision, and the distal tip may be advanced into thesame entry into Schlemm's canal. The method described above may then berepeated on the second half of Schlemm's canal to cut through thetrabecular meshwork. In some instances, viscoelastic may be used totamponade any blood reflux back into the anterior chamber.

At the end of the procedure, the anterior chamber may be irrigated(e.g., with balanced salt solution) through the corneal wound (eithermanually or automated). A balanced salt solution or viscoelastic may beused to reform the anterior chamber as needed to achieve physiologicpressure and further tamponade any blood reflux from the collectorchannels back into the anterior chamber. If necessary, a suture may beused to seal the corneal or scleral incision. Postoperatively, anantibiotic or antiseptic, mydriatic agent, or a miotic agent, may beused as appropriate. For example, a miotic eye drop may be used forweeks or months to help prevent synechiae formation and angle closure.

In yet further methods, tissue disruption may be accomplished by theab-interno delivery of a suture throughout Schlemm's canal, which isthen sufficiently tensioned to stretch the canal, disrupt the trabecularmeshwork, and/or tear through the meshwork (“ab-interno suturetrabeculotomy”). Here a tool including a grasping element may beemployed for pulling the distal suture tip inwards as the cannula isbeing withdrawn from the eye, severing all 360 degrees or a segment ofthe trabecular meshwork, or for tying the suture ends together toprovide tension on the meshwork without necessarily tearing it.

Ab-Externo Approach

An ab-externo approach to implanting an ocular device or delivering afluid composition may include additional or slightly different steps.For example, the creation of tissue flaps, suturing, etc., may be partof the ab-externo method. In general, the ab-externo method forimplanting an ocular device may include the following steps. First,under microscopic visualization, conjunctiva is incised, a scleral flapis created and tissue is dissected to identify the ostia into Schlemm'scanal. The anterior chamber may be separately infused with saline or mayhave a viscoelastic composition placed in it to prevent collapse of theanterior chamber angle. The operation may be done as a standaloneprocedure or in combination with cataract surgery in one sitting. It mayalso be done before the cataract surgery portion or after it.

Using the delivery system described herein, the cannula may be advancedinto Schlemm's canal and the ocular device advanced using thepositioning element under direct microscopic visualization or through agonioscope or gonioprism. When the ocular device is advanced the desiredamount, the surgeon may release the ocular device from the positioningelement by actuating the engagement mechanism and remove the deliverysystem from the eye and operating field. The scleral wound may beself-sealing, or it may then be closed, using for example, sutures ortissue adhesive. If repositioning of the ocular device is needed ordesired, the surgeon may retract and/or advance the ocular device usingthe positioning element of the delivery system.

With respect to the delivery of a fluid composition, the ab-externomethod is similar to ab-interno delivery. However, instead of using apositioning element, the delivery system employs a slidable elongatemember to infuse a fluid composition into Schlemm's canal. First, undermicroscopic visualization, conjunctiva is incised, a scleral flap iscreated and tissue is dissected to identify the ostia into Schlemm'scanal. The anterior chamber may be separately infused with saline or mayhave a viscoelastic composition placed in it to prevent collapse of theanterior chamber angle. The operation may be done as a standaloneprocedure or in combination with cataract surgery in one sitting. It mayalso be done before the cataract surgery portion or after it.

Using the delivery system described herein, the cannula may be advancedinto Schlemm's canal and a elongate member coaxially disposed within thecannula lumen may be advanced into the canal under gonioscopicvisualization. Once the elongate member has been positioned within thecanal, a fluid composition, e.g., a viscoelastic fluid, may becontinuously or intermittently delivered through the elongate member.The fluid composition may exit the lumen of the elongate member throughits distal end (e.g., the through the distal tip), or through openingsor fenestrations provided along its shaft, or a combination of both. Theopenings or fenestrations may be spaced along the axial length of theelongate member in any suitable manner, e.g., symmetrically orasymmetrically along its length. Other substances such as drugs, air, orgas may be delivered in the same manner if desired. The elongate membermay be repositioned by retraction or repeated advancement andretraction. The delivery system may then be removed from the eye.

The configuration of the ocular delivery system may be advantageous inmany different respects. In one aspect, the delivery system is capableof being used in an ab-interno method of implanting an ocular device inSchlemm's canal or an ab-interno method of delivering a fluidcomposition or a tool into the canal. In another aspect, the deliverysystem cannula is configured to allow easy and atraumatic access toSchlemm's canal. Furthermore, the delivery system is configured in amanner that gives the surgeon greater freedom of use, all in a singleinstrument. For example, the handle of the system is configured so thatit can be used with either side up (i.e., by flipping over the handle orrotating the cannula). Thus, the delivery system is designed to be usedin a clockwise or counterclockwise direction with either hand and ineither eye. For example, the delivery system is capable of being usedwith the right or left hand to access Schlemm's canal in acounterclockwise fashion, or used with the right left hand to access thecanal in a counterclockwise fashion, in either eye. Thus, access to thecanal from all four quadrants of the eye can be achieved. In yet afurther respect, the delivery system comprises single-handed,single-operator controlled devices configured to provide a forcesufficient to disrupt Schlemm's canal and surrounding tissues to improveflow through the trabeculocanalicular outflow pathway. The systemsgenerally combine access cannulas, delivery elongate members, elongatemember advancement mechanisms, disruptive tools, and viscoelastic fluidsinto a single device so that one person or one hand can advance theelongate member or tool, or deliver the fluid.

Methods of Manufacturing the Cannula

As mentioned above, the cannulas described here may be configured toboth pierce the trabecular meshwork or other tissue, and reversiblydeliver the elongate member without cutting, breaking, or otherwisedamaging the elongate member. In order to accomplish this dual purpose,the cannulas may be manufactured to comprise distal ends with both sharpand dull or blunt portions. Generally, methods of manufacturing thecannulas described here may comprise creating a bevel at a distal tip ofthe cannula, sharpening the distal end of the distal tip to create asharpened piercing tip, smoothing a portion of the distal tip of thecannula, and bending a portion of the cannula along a longitudinal axisof the cannula. In some variations, methods may also comprise acquiringa cannula of an appropriate working length, roughening an outer surfaceof the cannula, applying a protective covering to a portion of thedistal tip, polishing a portion of the cannula, and cleaning thecannula.

FIG. 19 depicts an exemplary method of manufacturing a cannula for usewith the devices, systems, and methods described here. As shown there, amethod of manufacturing the cannula (1900) may comprise acquiring acannula of an appropriate working length (1902), roughening an outersurface of the cannula (1904), creating a bevel at a distal tip of thecannula (1906), sharpening the distal tip of the cannula (1908),applying a protective covering to a portion of the distal tip of thecannula (1910), smoothing a portion of the distal tip of the cannula(1912), bending the cannula (1914), polishing the cannula (1916), andcleaning the cannula (1918). It should be appreciated that while themethod steps in FIG. 19 are depicted in a particular order, many of thesteps may be completed in a different order, and some of the steps maybe optional all together, as is discussed in more detail below.

To begin the process, a cannula of a suitable working length may beacquired (1902). The cannulas may be purchased pre-cut to a desiredworking length, or the raw material used to create the cannulas, forexample, stainless steel hypodermic tubing, may be purchased in bulkquantities and cut to the appropriate length during the cannulamanufacturing process. The cannulas may be examined for damage or othervisual defects upon acquisition and throughout the manufacturingprocess. In some variations, the working length (i.e., a length suitablefor handling the cannula during manufacturing) may correspond to thefinal desired length of the cannula. In other variations, for ease ofmanufacturing for example, the working length may be longer than thedesired length, and the cannula may be cut or shortened to the finaldesired length at any point during the manufacturing process (e.g., bycutting the proximal end of the cannula), including as the last step ofthe process. Exemplary working lengths include, but are not limited to,between about 50 mm and about 70 mm, between about 40 mm and about 90mm, and more specifically, about 60 mm.

The proximal end of the cannula may be cut, treated, and/or finished atany time during the manufacturing process. In some instances, theproximal end of the cannula may be square cut (i.e., cut substantiallyperpendicular to the longitudinal axis of the cannula). The edges of theproximal end may be smoothed or rounded using any suitable method, forexample, by media blasting. This smoothing of the proximal end of thecannula may prevent cutting, tearing, or otherwise damaging the elongatemember. For example, smoothing the proximal end may remove any sharpedges or jagged surfaces therefrom, and may remove any debris ordeposits remaining in the proximal end of the lumen from the cuttingprocess. The proximal end of the cannula may be inspected aftersmoothing, and if sharp or serrated edges remain, the proximal end maybe further smoothed.

In some variations, an outer surface of the cannula may optionally beroughened (1904) or texturized, which may assist in adhering the cannulato the handle. For example, in some instances, a proximal or centralportion of an outer surface of the cannula may be abrasively blasted tocreate a textured or rough surface to which adhesive may be applied.Abrasively blasting an outer surface of the cannula may increase thesurface area of the abrasively blasted portions, which may provide forbetter adhesion between the handle and the cannula.

As described above, the distal end of the cannula may be beveled. Thebevel may be created (1906) by cutting or grinding the distal end of thecannula at an angle relative to the longitudinal axis of the cannula.More specifically, the bevel may be installed such that it traverses andis transverse to the lumen of the cannula. FIG. 3 depicts a side view ofa cannula (300) comprising a bevel (312) at its distal tip (306). Thebevel (312) may comprise an angle (A) between about 5 degrees and about85 degrees. As mentioned above, the angle (A) may be important toproperly puncture the trabecular meshwork and access Schlemm's canalwithout damaging other surrounding tissue, and/or to adequatelyvisualize advancement and retraction of the elongate member. In somevariations, the angle (A) may be about 5, 10, 15, 20, 25, 30, 35, 40,45, 50, 55, 60, 65, 70, 75, 80, or 85 degrees. In some variations, theangle (A) may be between about 23 degrees and about 27 degrees. In someof these variations, the angle (A) may be about 25 degrees.

FIG. 20 depicts a perspective view of a distal tip (2002) of a cannula(2000) after a bevel has been created. As shown, the beveled distal tip(2002) now comprises a proximal end (2008) and a distal end (2010).Additionally, creating the bevel at the distal tip (2002) may elongatethe opening (2012) at the distal tip (2002) creating an elliptical,rather than circular, shaped opening. Thus, beveling the distal tip(2002) may yield an elliptical shaped lumen opening that is angled suchthat the top of the elliptical opening is closer to the proximal portionof the cannula than the bottom of the elliptical opening. Also shown inFIG. 20 are inner and outer circumferential edges (2004, 2006).

Although installing the bevel may create sharp edges, and in someinstances, a sharp distal tip, it may be desirable to further sharpen aportion of the distal tip of the cannula to achieve easier access intoSchlemm's canal with higher precision. Accordingly, in some instances,after the bevel has been created, the distal tip may be furthersharpened (1908) to create a sharpened piercing tip that may furtherassist in piercing the trabecular meshwork. The distal tip may besharpened using any suitable means, for example, by grinding orotherwise removing a portion of the external surface and/or a portion ofthe outer circumferential edge of the distal end of the distal tip ofthe cannula. To minimize unwanted sharp edges that may damage theelongate member, it may be desirable to maintain as much of the wallthickness at the distal tip as possible, and to ensure that thethickness of the wall is uniform. It may also be beneficial to preventcannula material or other sharpening byproducts from forming,building-up, adhering to, or otherwise being deposited on an internalsurface of the cannula in the lumen. Such materials may become debriscreate raised or sharp surfaces or edges that may cut or damage theelongate member when the delivery system is in use.

FIGS. 21A and 21B depict perspective and front views, respectively, of avariation of a distal tip (2100) of a cannula comprising both a bevel(2102) and a sharpened piercing tip (2114). The distal tip (2100) alsocomprises a proximal end (2108), a distal end (2110), inner and outercircumferential edges (2104, 2106), and a lumen opening (2112). Thesharpened piercing tip (2114) may be created by grinding the distal end(2110) of the distal tip (2100), thereby creating two angled surfaces(2116) that converge to form a sharp point. The angled surfaces (2116)may be formed at any suitable angle that results in a sharpened piercingtip (2114). For example, in some instances, the angle surfaces (2116)may have an angle (B) relative to the longitudinal axis of the distaltip (2100) of about 20, 25, 30, 35, 40, 45, or 50 degrees, between about25 and about 50 degrees, or between about 37.5 and about 42.5 degrees.Accordingly, in some variations, the angle between the two angledsurfaces (2116) may be between about 50 and about 100 degrees. It shouldbe appreciated that although the distal tip (2100) is depicted with twoangled surfaces, a distal tip with a single angled surface may also beused.

Turning back to FIG. 19, the method for manufacturing the cannula (1900)may further comprise smoothing a portion of the distal tip (1912) of thecannula. In variations in which the distal tip of the cannula issharpened, as described above with respect to FIGS. 21A and 21B, themethod may further comprise applying a protective covering (1910) overthe sharpened portion of the distal tip, for example, the distal end ofthe sharpened piercing tip (2114) and/or the angled surfaces (2116),prior to smoothing the distal tip (1912). In variations in which thedistal tip is not sharpened after it is beveled, it may still bedesirable to apply a protective covering over the distal end of thedistal tip (as described with respect to FIG. 20 above). Applying aprotective covering may help to maintain the sharp edge(s) duringsmoothing.

As mentioned above, the distal tip of the cannula may be configured toboth pierce tissue, and to deliver a elongate member. The elongatemember itself may be susceptible to being pierced, cut, severed, orotherwise damaged by the cannula. In order to protect the elongatemember, it may be important to smooth or deburr the surfaces and/oredges of the distal tip of the cannula that the elongate member maycontact. For example, referring again to FIGS. 21A and 21B, in somevariations, a portion of the inner and/or outer circumferential edges(2104, 2106), the surface between the edges (2118), and/or the internaland/or external surfaces of the cannula adjacent to the opening (2112),may be smoothed. This may even out and/or dull these edges and surfaces.For example, it may be desirable to smooth a portion of the innercircumferential edge (2104) at the proximal or distal end (2108, 2110)of the distal tip (2100), or to smooth the entire inner circumferentialedge. In some instances, a portion of the outer circumferential edge(2106) may also be smoothed while maintaining the sharp edges of thedistal tip (e.g., the sharpened piercing tip). For example, a portion ofthe outer circumferential edge (2106) may be smoothed at the proximalend (2108) of the distal tip (2100), or the entire outer circumferentialedge (2106), up to the angled surfaces (2116) may be smoothed.Additionally, it may be desirable to smooth or deburr the surfacebetween the edges (2118) and/or the internal or external surface of thecannula adjacent to the opening (2112) at the proximal end (2108) ordistal end (2110) of the distal tip (2100), or circumferentially aroundthe opening (2112).

Portions of the distal tip (2100) of the cannula may be deburred,smoothed, evened, rounded, dulled, or the like, using any suitablemechanism. For example, smoothing portions of the distal tip of thecannula may comprise mechanical and/or manual deburring, abrasive orsoda media blasting, sanding, grinding, wire brushing, laser ablating,polishing (e.g., electropolishing), a combination thereof, or the like.

Turning back to FIG. 19, the method of manufacturing a cannula (1900)may further comprise bending a distal portion of the cannula (1914) toform the distal curved portion described above. Bending the catheter mayproperly orient the distal tip such that it may atraumatically puncturethe trabecular meshwork. Referring back to FIG. 3, in some variations,the distal portion of the cannula may be bent such that the sharpenedpiercing tip is located along the outer radius (322) of the curvedcannula. In some instances, the distal portion of the cannula may bebent to an angle between about 100 and about 125 degrees, about 115 andabout 125 degrees, or to about 118 degrees relative to an externalsurface of a proximal portion of the cannula.

The distal portion of the cannula may be bent using any suitablemechanical or manual bending process. It may be important to select abending process that does not alter the cross-sectional size and shapeof the cannula during the bending process. Additionally, it should beappreciated that the cannula may be bent at any point in themanufacturing process, and bending need not occur after the distal tipof the cannula is smoothed, as depicted in the method (1900) in FIG. 19.

The method of manufacturing a cannula (1900) may optionally comprisepolishing (1916) all or a portion of the cannula, for example, thedistal tip of the cannula. In variations in which the cannula ispolished, polishing the cannula (1916) may remove debris, markings,indentations, grooves, or the like, left on the surfaces of the cannula.These markings may be remnants from any part of the manufacturingprocess, and specifically may be from creating the bevel at the distaltip of the cannula (1906), sharpening the distal tip of the cannula(1908), and/or smoothing a portion of the distal tip of the cannula(1912). Polishing the cannula (1916) may be especially useful invariations in which smoothing a portion of the distal tip of the cannula(1912) comprises a process that generally leaves debris or markingsbehind, for example, laser ablation. Polishing the cannula (1916) may becompleted using any suitable method, for example, electropolishing,staged media blasting using media with increasing grain size, or thelike.

If desired, the cannula may be cleaned (1918) prior to its installationinto the delivery systems described here. For example, in somevariations, the cannula may be passivated to remove iron oxide or othercontaminants. In some instances, the cannula may be passivated using anacid like, for example, nitric oxide. In other variations, the cannulamay be cleaned using cleansers, ultrasonic baths, or any other suitablecleaning process.

The cannula and/or the assembled delivery system may be sterilized, forexample, using gamma irradiation. The gamma irradiation dose range maybe, for example, between 25-40 kGy. Other irradiation energies may beused for sterilization, for example e-beam irradiation. Alternativesterilization methods include gas sterilization, for example ethyleneoxide gas sterilization. In variations in which all or a portion of thesystems are reusable, as described herein, these portions may besterilized and reused. For example, in variations in which the handle isreusable and the cannula and elongate member are disposable, after usethe used cannula and elongate member may be removed, the handlesterilized, and a new cannula and elongate member attached to thesterile handle.

While the inventive devices, systems, kits, and methods have beendescribed in some detail by way of illustration, such illustration isfor purposes of clarity of understanding only. It will be readilyapparent to those of ordinary skill in the art in light of the teachingsherein that certain changes and modifications may be made theretowithout departing from the spirit and scope of the appended claims.

The invention claimed is:
 1. A method for treating a condition of an eyecomprising: advancing a distal end of a device comprising an elongatemember and a fluid assembly coupled to a linear gear via a linkage intoan anterior chamber of the eye; advancing the elongate member intoSchlemm's canal by advancing the linear gear and the fluid assembly,wherein the linkage maintains a fixed distance between the linear gearand the fluid assembly during advancement; and retracting the elongatemember and simultaneously delivering a fluid composition through theelongate member into Schlemm's canal by retracting the linear gearwithout retracting the fluid assembly or the linkage.
 2. The method ofclaim 1 further comprising tearing a trabecular meshwork of the eye. 3.The method of claim 2, wherein the trabecular meshwork is torn by theelongate member.
 4. The method of claim 3, wherein the trabecularmeshwork is torn by a body of the elongate member.
 5. The method ofclaim 2, wherein the elongate member is advanced a first length aroundSchlemm's canal, and wherein the fluid composition is delivered to thesame first length around Schlemm's canal.
 6. The method of claim 5,wherein the trabecular meshwork is torn along the same first lengtharound Schlemm's canal.
 7. The method of claim 6, wherein the trabecularmeshwork is torn by the elongate member.
 8. The method of claim 5,wherein the trabecular meshwork is torn along a length other than thefirst length around Schlemm's canal.
 9. The method of claim 2, whereinthe elongate member is advanced about 180 degrees around Schlemm's canalin a first direction.
 10. The method of claim 9 further comprising:advancing the elongate member about 180 degrees around Schlemm's canalin a second direction; and retracting the elongate member andsimultaneously delivering a fluid composition through the elongatemember.
 11. The method of claim 10 further comprising tearing thetrabecular meshwork a second time.
 12. The method of claim 10, whereintearing the trabecular meshwork comprises tearing the trabecularmeshwork around Schlemm's canal in the first direction and tearing thetrabecular meshwork around Schlemm's canal in the second direction. 13.The method of claim 12, wherein tearing the trabecular meshwork in thefirst direction comprises tearing the trabecular meshwork 180 degreesaround Schlemm's canal in the first direction.
 14. The method of claim13, wherein tearing the trabecular meshwork in the second directioncomprises tearing the trabecular meshwork 180 degrees around Schlemm'scanal in the second direction.
 15. The method of claim 10, whereinadvancing the elongate member into Schlemm's canal moves the fluidassembly distally to a first position, and wherein advancing theelongate member into Schlemm's canal in the second direction moves thefluid assembly from the first position distally to a second position.16. The method of claim 1, wherein between about 2 microliters and about9 microliters of the fluid composition are delivered to Schlemm's canal.17. The method of claim 16, wherein about 4.5 microliters of the fluidcomposition are delivered to Schlemm's canal.
 18. The method of claim 9,wherein about 10 microliters of the fluid composition are delivered toSchlemm's canal.
 19. The method of claim 10, wherein about 20microliters of the fluid composition are delivered to Schlemm's canal intotal.
 20. The method of claim 1, wherein the device further comprises ahousing and a lock configured to restrict movement of the fluid assemblyrelative to the housing prior to use, and the method further comprisesdisengaging the lock to allow movement of the fluid assembly relative tothe housing.
 21. The method of claim 1, wherein the device furthercomprises a housing, and wherein the fluid assembly moves distally, butnot proximally, relative to the housing.
 22. The method of claim 21,wherein the housing comprises teeth that allow the fluid assembly tomove distally relative to the housing during advancement of the elongatemember and that fix the fluid assembly relative to the housing duringretraction of the elongate member.
 23. The method of claim 1, whereinthe fluid assembly comprises a luer fitting or a one-way valve fortransfer of the fluid composition into the fluid assembly.
 24. Themethod of claim 1, wherein retracting the elongate member and deliveringthe fluid composition are both actuated by rotation of a wheel.
 25. Amethod for treating a condition of an eye comprising: advancing a distalend of a device comprising an elongate member and a fluid assemblycoupled to a linear gear via a linkage into an anterior chamber of theeye; advancing the elongate member into Schlemm's canal in a firstdirection by advancing the linear gear and the fluid assembly;retracting the elongate member and simultaneously delivering a fluidcomposition through the elongate member into Schlemm's canal byretracting the linear gear without retracting the fluid assembly or thelinkage; advancing the elongate member into Schlemm's canal in a seconddirection by advancing the linear gear and the fluid assembly a secondtime; retracting the elongate member and simultaneously delivering afluid composition through the elongate member into Schlemm's canal byretracting the linear gear without retracting the fluid assembly or thelinkage a second time; and tearing the trabecular meshwork along thefirst direction and the second direction, wherein the linkage maintainsa fixed distance between the linear gear and the fluid assembly duringadvancement.